Vitamin D3 derivative and treating agent for inflammatory respiratory disease using same

ABSTRACT

Provided are vitamin D 3  derivatives expressed by the following general formula [1] ##STR1## [wherein, R 1  and R 2  are each a hydrogen atom, a trialkylsilyl group, an acetyl group, a methoxymethyl group, or a tetrahydropyranyl group; R 3  and R 4  are each a hydrogen atom, a hydroxyl group, an acyloxy group, an alkyloxy group, an alkylthio group or an alkyl group which is optionally substituted; R 5 , R 6 , R 7  and R 8  are each a hydrogen atom, a hydroxyl group, an alkyl group or an acyloxy group; R 9  is a hydrogen atom, a hydroxyl group, an alkyl group or an alkylthio group; R 10  is a hydrogen atom, an alkyl group or an alkyloxy group; A and B are each a hydrogen atom, a hydroxyl group, or together express a single bond; X and Y express a carbonyl oxygen, or one of them is a hydrogen atom and the other is a hydroxyl group or an acyloxy group; n is an integer of 0 to 2; m is an integer of 0 to 2], and a method for manufacturing the derivatives. 
     The compounds can be sued as active ingredients of treating agents for inflammatory respiratory diseases, malignant tumors, rheumatoid arthritis, osteoporosis, diabetes mellitus, hypertension, alopecia, acne, psoriasis and dermatitis.

TECHNICAL FIELD

The present invention relates to vitamin D₃ derivatives useful aspharmaceutical products or pharmaceutically permissible solvatesthereof, treating agents using same, pharmaceutical compositionscontaining same, and a method for manufacturing same. More particularly,the invention relates to 1 α-hydroxyvitamin D₃ derivatives havingneutrophilic infiltration-suppressing activity, the growth suppressionand differentiation induction of malignant tumor cells, etc., orpharmaceutically permissible solvates thereof, treating agents forinflammatory respiratory diseases, malignant tumors, etc., containingsame as active ingredients, pharmaceutical compositions containing sameand a method for manufacturing same.

BACKGROUND ART

An active vitamin D₃ derivative has calcium absorption-stimulatingactivity in the small intestine, and activity such as the control ofbone resorption and osteogenesis in the bones, and it is used as atreating agent for diseases caused by various kinds of calciummetabolism disorders. In recent years, immunoregulatory activity, cellproliferation inhibitory activity and cell differentiation inductingactivity have been found besides these activities. For example,applications to a treating agent for rheumatoid arthritis (JapaneseUnexamined Patent Publication No. 56-26820), an antiallergic agent(Japanese Un-examined Patent Publication No. 63-107928, English PatentPublica-tion No. 2260904(GB 2260904-A)), a treating agent for psoriasis(Japanese Unexamined Patent Publication No. 3-68009), a treating agentfor diseases attributable to thromboxane A₂ production (JapaneseUnexamined Patent Publication No. 5-294834), a treating agent for eczemaand dermatitis (Japanese Unexamined Patent Publication No. 7-291868),etc., are being studied.

On the other hand, respiratory tract infection is a disease which isestablished when pathogens invade getting over infection preventingmechanisms of the respiratory tract, and the treatment is mainly basedon the improvement of respiratory tract clearance by using abronchodilator, an expectorant, etc. But, in the case of acuteexacerbation with infection, the main treatment is a strongantibacterial treatment against phlogogenic bacteria. However, mostunderlying diseases constantly becomes worse when acute exacerbation isrepeated. Further, present treatments, which depends on antibacterialagents in the extreme, are under reconsideration owing to the emergenceof resistant bacteria such as MRSA.

Recently, the usefulness of a low-dose long administration oferythromycin for a chronic lower airway infectious disease has beenreported, and it is attracting attention. A chronic lower airwayinfectious disease is a generic name for bacterial infections observedin chronic bronchitis, diffuse panbronchiolitis, bronchiectasis, etc.,(sometimes, it includes bronchial asthma, chronic pulmonary emphysema,pulmonary tuberculosis sequela, etc., accompanied by infection).Although these are different in the name of disease, it is known thatall of the diseases take common morbid states such as purulent sputum inlarge amount, fatigue dyspnea and hypoxemia. Regarding the workingmechanism of erythromycin, it is understood that erythromycin's functiondoes not depend simply on its antibacterial activity, namely,erythromycin acts not on bacteria themselves but rather on inflammatorycells which accumulate on the airway accompanied by the bacteria,especially acts on neutrophils. That is, neutrophils infiltrate intotissues by the various kinds of stimulation caused by the infection torelease protease as well as active oxygen, and these substances causeepithelium damage, the trouble of ciliary movement and mucosahypersecretion to exert a bad influence upon respiratory physiologicaleffect, and erythromycin acts on these processes. Based on suchconsideration, a medicine, which suppresses the pulmonary tissueinfiltration of neutrophils or suppresses the activity of neutrophils,can be useful as a treating agent for inflammatory dyspnea, for example,chronic lower airway infectious disease.

Further, regarding the effect on malignant tumor cells, it has beenreported that an active vitamin D₃ derivative has various physiologicalactivities such as proliferation suppression, differentiation inductionand regulatory effect on immunological function. For example, it hasbeen reported that an active vitamin derivative D₃ exhibitsproliferation suppressing effect or differentiation inducing effect onleukemic cells (Cancer Treatment Reports, 69, 1399-1407 (1985), andCancer Res., 43, 5862-5867 (1983)), colon cancer cells (Gut, 33,1660-1663 (1992), and Jpn. J. Cancer Res., 88, 1052-1062 (1997)),mammary tumor cells (Cancer Res., 53, 2534-2537 (1993), prostatic cancercells (Endocrinology, 132, 1952-1960 (1993)), etc. In addition,regarding the occurrence of human colon cancer, there is a report on thecorrelation between the rate of the occurrence and the uptake of vitaminD₃ (Lancet, 1, 307-309 (1985)).

Treatments of malignant tumors are important problems at therapy sites,and a number of treating agents for malignant tumors have beendeveloped. However, most of the mechanisms of action of these treatingagents are based on cell functional disorders, and serious side effectsare often accompanied. Further, there is no effective treating agent forsome kinds of malignant tumors. On these circumstances, the developmentof a treating agent for malignant tumor which exhibits a therapeuticeffect based on a mechanism of action different from those ofconventional treating agents and has little side effect is eagerlywaited for.

Although therapeutic effects of vitamins Ds, especially active vitaminD₃ and its derivatives on malignant tumors have been studied up to now(for example, Japanese Unexamined Patent Publication No. 57-149224),sufficient therapeutic effect has not been attained due to the fact thathypercalcemia, which is considered attributable to a characteristicphysiological action of vitamins Ds, causes serious side effects inactual human therapy. For developing these compounds as treating agentsfor malignant tumors, it is therefore assumed to be effective to usecompounds which do not induce hypercalcemia while keeping proliferationsuppressing effect and differentiation inducing effect of vitamins Ds onthe malignant tumors.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide new vitamin D₃derivatives effective as treating agents for inflammatory respiratorydiseases, which have suppressing effect on neutrophilic infiltrationwithout inducing hypercalcemia.

Another object of the present invention is to provide new vitamin D₃derivatives effective as treating agents for malignant tumors, whichhave growth-suppressing and differentiation-inducing effects onmalignant tumor cells without inducing hypercalcemia.

Still another object of the present invention is to provide therapeuticmethods for treating inflammatory respiratory diseases by using thesevitamin D₃ derivatives as active ingredients.

Yet another object of the present invention is to provide therapeuticmethods for treating malignant tumors by using these vitamin D₃derivatives as active ingredients.

A further object of the present invention is to provide pharmaceuticalcompositions composed of these vitamin D₃ derivatives as activeingredients.

A still further object of the present invention is to provide a methodfor producing these vitamin D₃ derivatives.

According to the present invention, the above objects of the presentinvention are achieved by vitamin D₃ derivatives expressed by thefollowing general formula [1]: ##STR2## [wherein, Z is 1a, 1b or 1c; R₁and R₂ are identical to or different from each other, and are each ahydrogen atom, a tri(C₁ -C₇ alkyl)silyl group, an acetyl group, amethoxymethyl group, or a tetrahydropyranyl group; R₃ and R₄ areidentical to or different from each other, and are each a hydrogen atom,a hydroxyl group, a C₂ -C₈ acyloxy group, a C₁ -C₇ alkyloxy group, a C₁-C₆ alkylthio group or a C₁ -C₇ alkyl group which is optionallysubstituted with a hydroxyl group, a C₂ -C₈ acyloxy group or a C₁ -C₇alkyloxy group; R₅, R₆, R₇ and R₈ are identical to or different fromeach other, and are each a hydrogen atom, a hydroxyl group, a C₁ -C₇alkyl group or a C₂ -C₈ acyloxy group; R₉ is a hydrogen atom, a hydroxylgroup, a C₁ -C₇ alkyl group or a C₁ -C₆ alkylthio group; R₁₀ is ahydrogen atom, a C₁ -C₇ alkyl group or a C₁ -C₇ alkyloxy group; A and Bare identical to or different from each other, and are each a hydrogenatom, a hydroxyl group, or together express a single bond and express adouble bond in cooperation with the single bond already shown in theformula (later, this may be expressed "A and B together express a doublebond as a whole"); X and Y together express a carbonyl group incooperation with the carbon atom to which they are bonded, one of themis a hydrogen atom and the other is a hydroxyl group, or one of them isa hydrogen atom and the other is a C₂ -C₈ acyloxy group; n is an integerof 0 to 2; m is an integer of 0 to 2], or pharmaceutically permissiblesolvates thereof.

The configuration of the carbon atom at the 20-position in the aboveformula [1] may be (S)-configuration or (R)-configuration. When a carbonatom to which R₃ and R₄, R₅ and R₆, R₇ and R₈, X and Y, or A and B arebonded becomes an asymmetric center, the configuration of the carbonatom may be (S)-configuration or (R)-configuration. Further, when A andB together express a double bond as a whole, the configuration of thedouble bond may be (E)-configuration or (Z)-configuration. Furthermore,the present invention includes a mixture of such stereoisomers atarbitrary ratios.

In addition, according to the present invention, above objects of thepresent invention are achieved by therapeutic methods for inflammatoryrespiratory diseases using above vitamin D₃ derivatives orpharmaceutically permissible solvates thereof in therapeuticallyeffective amounts as active ingredients.

Further, according to the present invention, above objects of thepresent invention are achieved by therapeutic methods for malignanttumors using the above vitamin D₃ derivatives or pharmaceuticallypermissible solvates thereof in therapeutically effective amounts asactive ingredients.

Further, according to the present invention, the above objects of thepresent invention are achieved by pharmaceutical compositions consistingof the above vitamin D₃ derivatives or pharmaceutically permissiblesolvates thereof, and pharmaceutically permissible supports.

Furthermore, according to the present invention, the above objects ofthe present invention are achieved by a method for producing activevitamin D₃ derivatives in which vitamin D₃ derivatives whose hydroxylgroups at the first- and the third-positions are each protected with atri(C₁ -C₇ alkyl)silyl group are treated with a reagent consisting of acombination of a tetrafluoroborate alkali metal salt and a mineral acidfor deprotection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing showing calcium concentrations in blood measuredafter the oral repeated administrations of an active vitamin D₃ (1 α,25(OH)₂ D₃) or a compound (No. 1126b) of the present invention for twoweeks to mice in which human malignant tumor cells have beentransplanted under the renal capsule.

C: control group

*: statistically significant against the control group

(Dunnett method: significance level of 5%)

***: statistically significant against the control group

(Dunnett method: significance level of 0.01%)

FIG. 2 is a drawing showing sizes (tumor area) of transplanted cellaggregates determined after the oral repeated administrations of anactive vitamin D₃ (1 α, 25(OH)₂ D₃) or a compound (No. 1126b) of thepresent invention for 2 weeks to mice in which HL-60 cells have beentransplanted under the renal capsule.

C: control group

*: statistically significant against the control group

(Dunnett method: significance level of 5%)

FIG. 3 is a drawing showing sizes (tumor area) of transplanted cellaggregates determined after the oral repeated administrations of anactive vitamin D₃ (1 α, 25(OH)₂ D₃) or a compound (No. 1126b) of thepresent invention for 2 weeks to mice in which HT-29 cells have beentransplanted under the renal capsule.

C: control group

*: statistically significant against the control group

(Dunnett method: significance level of 5%)

***: statistically significant against the control group

(Dunnett method: significance level of 0.01%)

BEST MODE FOR CARRYING OUT THE INVENTION

Terms used in the present invention are defined as follows.

The term "alkyl group" refers to a normal or branched aliphatichydrocarbon group or an aromatic hydrocarbon group.

The term "alkyloxy group" refers to a normal or branched aliphatichydrocarbon-oxy group or an aromatic hydrocarbon-oxy group.

The term "acyl group" refers to a normal or branched aliphatichydrocarbon-carbonyl group or an aromatic hydrocarbon-carbonyl group.

The term "acyloxy group" refers to a normal or branched aliphatichydrocarbon-carbonyloxy group or a normal or branched aromatichydrocarbon-carbonyloxy group.

The term "alkylthio group" refers to a normal or branched aliphatichydrocarbon-thio group or an aromatic hydrocarbon-thio group.

In the above formula [1], Z is 1a, 1b or 1c. Among them is preferable 1aor 1b.

In the above formula [1], R₁ and R₂ are identical to or different fromeach other, and are each a hydrogen atom, a tri(C₁ -C₇ hydrocarbon)silylgroup, an acetyl group, a methoxymethyl group, or a tetrahydropyranylgroup. Among them is most preferable the case where both of R₁ and R₂are hydrogen atoms.

Further, when R₁ and R₂ are each a tri(C₁ -C₇ alkyl)silyl group, forexample, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl and tribenzylsilyl groups, etc., may be cited aspreferable concrete examples.

In the above formula [1], R₃ and R₄ are identical to or different fromeach other, and are each a hydrogen atom, a hydroxyl group, a C₂ to C₈acyloxy group, a C₁ to C₇ alkyloxy group, a C₁ -C₆ alkylthio group or aC₁ -C₇ alkyl group which is optionally substituted with a hydroxylgroup, a C₂ -C₈ acyloxy group or a C₁ -C₇ alkyloxy group.

When R₃ and R₄ are each a C₁ -C₇ alkyloxy group, for example, methoxy,ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, s-butyloxy,t-butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxyand benzyloxy groups, etc., may be cited as concrete examples. Amongthese groups are preferable methoxy, ethoxy, propyloxy, isopropyloxy,butyloxy, isobutyloxy, s-butyloxy, t-butyloxy and benzyloxy groups.Especially, methoxy, ethoxy and propyloxy groups are most preferablemethoxy.

When R₃ and R₄ are each a C₁ -C₆ alkylthio group, for example,methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio,neopentylthio, hexylthio, heptylthio and phenylthio groups, etc., may becited as concrete examples. Among these groups are preferable C₁ -C₄alkylthio groups, for example, methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, s-butylthio and t-butylthiogroups. Especially, methylthio, ethylthio and propylthio groups are mostpreferable.

When R₃ and R₄ are each a C₂ -C₈ acyloxy group, for example, acetoxy,propionyloxy, isopropionyloxy, butyryloxy, isobutyryloxy, s-butyryloxy,valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy and benzoyloxygroups, etc., may be cited as concrete examples. Among these groups arepreferable C₂ -C₄ acyloxy groups, for example, acetoxy, propionyloxy,isopropionyloxy, butyryloxy, isobutyryloxy, s-butyryloxy and benzoyloxygroups.

When R₃ and R₄ are each a C₁ -C₇ alkyl group which is optionallysubstituted with a hydroxyl group, a C₂ -C₈ acyloxy group or a C₁ -C₇alkyloxy group, the C₁ -C₇ alkyl group may be substituted with ahydroxyl group, a C₂ -C₈ acyloxy group or a C₁ -C₇ alkyloxy group at anyposition. As concrete examples of such alkyl groups, for example,methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, benzyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl,hydroxyhexyl, hydroxyheptyl, hydroxybenzyl, acetoxymethyl,propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, acetoxyethyl,propionyloxyethyl, butyryloxyethyl, benzoyloxyethyl, acetoxypropyl,propionyloxypropyl, butyryloxypropyl, benzoyloxypropyl, methoxymethyl,ethoxymethyl, benzyloxymethyl, methoxyethyl, ethoxyethyl,benzyloxyethyl, methoxypropyl, ethoxypropyl and benzyloxypropyl groups,etc., may be cited. Among these groups are preferable methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, benzyl,hydroxymethyl, hydroxyethyl, hydroxybenzyl, acetoxymethyl,benzoyloxymethyl, acetoxyethyl, benzoyloxyethyl, acetoxypropyl,benzoyloxypropyl, methoxymethyl, benzyloxymethyl, methoxyethyl,benzyloxyethyl, methoxypropyl and benzyloxypropyl groups. Especially,methyl, ethyl, propyl, benzyl, hydroxymethyl, methoxymethyl andbenzyloxymethyl groups are most preferable.

Further, preferable combinations of the R₃ and R₄ are follows: one of R₃and R₄ is a hydroxyl group, and the other is a C₁ -C₇ alkyl group whichis optionally substituted with a hydroxyl group, a C₂ -C₈ acyloxy groupor a C₁ -C₇ alkyloxy group; one of R₃ and R₄ is a hydrogen atom, and theother is a C₁ -C₇ alkyl group which is optionally substituted with ahydroxyl group, a C₂ -C₈ acyloxy group or a C₁ -C₇ alkyloxy group; bothof R₃ and R₄ are each a hydrogen atom; or both of R₃ and R₄ are each aC₁ -C₇ alkyl group, which is optionally substituted with a hydroxylgroup, a C₂ -C₈ acyloxy group or a C₁ -C₇ alkyloxy group, in whichsubstituents are same or different in R₃ and R₄.

In the above formula [1], R₅, R₆, R₇ and R₈ are identical to ordifferent from each other, and are each a hydrogen atom, a hydroxylgroup, a C₁ -C₇ alkyl group or a C₂ -C₈ acyloxy group. Among them arepreferable a hydrogen atom and a C₁ -C₇ alkyl group.

When R₅, R₆, R₇ and R₈ are each a C₁ -C₇ alkyl group, for example,methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl and benzyl groups maybe cited as concrete examples. Among them are preferable methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl groups.Especially, methyl, ethyl and propyl groups are preferable.

When R₅, R₆, R₇ and R₈ are each a C₂ -C₈ acyloxy group, for example,acetoxy, propionyloxy, isopropionyloxy, butyryloxy, isobutyryloxy,s-butyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy andbenzoyloxy groups, etc., may be cited as concrete examples. Among thesegroups are preferable C₂ -C₄ acyloxy groups, for example, acetoxy,propionyloxy, isopropionyloxy, butyryloxy, isobutyryloxy, s-butyryloxyand benzoyloxy groups.

In the above formula [1], R₉ is a hydrogen atom, a hydroxyl group, a C₁-C₇ alkyl group or a C₁ -C₆ alkylthio group.

When R₉ is a C₁ -C₇ alkyl group, for example, methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl,neopentyl, hexyl, heptyl and benzyl groups may be cited as concreteexamples. Among these groups are preferable C₁ -C₄ alkyl groups, forexample, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyland t-butyl groups. Especially, methyl, ethyl and propyl groups are mostpreferable.

When R₉ is a C₁ -C₆ alkylthio group, for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio,t-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio,heptylthio and phenylthio groups, etc., may be cited as concreteexamples. Among these groups are preferable C₁ -C₄ alkylthio groups, forexample, methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, s-butylthio and t-butylthio groups. Especially,methylthio, ethylthio and propylthio groups are most preferable.Further, besides the above groups, R₉ is preferably a hydrogen atom or ahydroxyl group.

In the above formula [1], R₁₀ is a hydrogen atom, a C₁ -C₇ alkyl groupor a C₁ -C₇ alkyloxy group, and among them, a hydrogen atom is

When R₁₀ is a C₁ -C₇ alkyl group, for example, methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl,neopentyl, hexyl, heptyl and benzyl groups, etc., may be cited asconcrete examples. Among these groups are preferable C₁ -C₄ alkylgroups, for example, methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl, s-butyl and t-butyl groups. Especially, methyl, ethyl andpropyl groups are most preferable.

Further, when R₁₀ is a C₁ -C₇ alkyloxy group, for example, methoxy,ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, s-butyloxy,t-butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxyand benzyloxy groups, etc., may be cited as concrete examples. Amongthese groups are preferable C₁ -C₄ alkyloxy groups, for example,methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,s-butyloxy and t-butyloxy groups. Especially, methoxy, ethoxy andpropyloxy groups are most preferable.

In the above formula [1], A and B are identical to or different fromeach other, and are each a hydrogen atom, a hydroxyl group, or togetherexpress a single bond. Among them are preferable the cases in which bothof A and B are each a hydrogen atom, A is a hydroxyl group and B is ahydrogen atom, and A and B together express a single bond. Especially,the cases in which both of A and B are each a hydrogen atom, and A and Btogether express a single bond are most preferable.

In the above formula [1], X and Y together form a carbonyl group incooperation with the carbon atom to which they are bonded, one of themis a hydrogen atom and the other is a hydroxyl group, or one of them isa hydrogen atom and the other is a C₂ -C₈ acyloxy group. Among them arepreferable the cases in which X and Y together form a carbonyl group incooperation with the carbon atom to which they are bonded, and one ofthem is a hydrogen atom and the other is a hydroxyl group.

When one of X and Y is a hydrogen atom and the other is a C₂ -C₈ acyloxygroup, for example, acetoxy, propionyloxy, isopropionyloxy, butyryloxy,isobutyryloxy, s-butyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy,heptanoyloxy and benzoyloxy groups, etc., may be cited as concreteexamples of the C₂ -C₈ acyloxy group. Among these groups are preferableC₂ -C₄ acyl groups, for example, acetoxy, propionyloxy, isopropionyloxy,butyryloxy, isobutyryloxy and s-butyryloxy groups.

In the formula [1], n is an integer of 0 to 2. Especially, n ispreferably 0 or 1.

In the formula [1], m is an integer of 0 to 2. Especially, m ispreferably 0 or 1.

Vitamin D₃ derivatives of the present invention can be optionallyconverted into pharmaceutically permissible solvates thereof. Examplesof a solvent to be used for such a purpose include water, methanol,ethanol, propyl alcohol, isopropyl alcohol, butanol, t-butanol,acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate,diethyl ether, t-butyl methyl ether, benzene, toluene, DMF, DMSO, etc.Especially, water, methanol, ethanol, propyl alcohol, isopropyl alcohol,acetonitrile, acetone, methyl ethyl ketone and ethyl acetate may becited as preferable examples.

Preferable concrete examples of a vitamin D₃ derivative of the presentinvention expressed by the above formula [1] are shown in Table 1-1 toTable 1-14 and Table 2-1 to Table 2-3. Further, in these compounds, theconfiguration of the carbon atom at the 20-position includes both(S)-configuration and (R)-configuration. When a carbon atom to which R₃and R₄, R₅ and R₆, R₇ and R₈, X and Y, or A and B are boned becomes anasymmetric center, the configuration of the carbon includes both(S)-configuration and (R)-configuration. Further, when A and B togetherexpress a double bond as a whole, the configuration of the double bondincludes both (E)-configuration and (Z)-configuration.

                                      TABLE 1-1                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B  X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                    __________________________________________________________________________    1101  0 0 double bond                                                                         carbonyl                                                                           H, H                                                                              H, H   H, H                                                                              H, H                                        1102 1 0 double bond carbonyl H, H H, H H, H H, H                             1103 2 0 double bond carbonyl H, H H, H H, H H, H                             1104 0 1 double bond carbonyl H, H H, H H, H H, H                             1105 1 1 double bond carbonyl H, H H, H H, H H, H                             1106 2 1 double bond carbonyl H, H H, H H, H H, H                             1107 0 2 double bond carbonyl H, H H, H H, H H, H                             1108 1 2 double bond carbonyl H, H H, H H, H H, H                             1109 2 2 double bond carbonyl H, H H, H H, H H, H                             1110 0 0 double bond carbonyl H, H H, Me H, H H, H                            1111 1 0 double bond carbonyl H, H H, Me H, H H, H                            1112 0 0 double bond carbonyl H, H H, Et H, H H, H                            1113 1 0 double bond carbonyl H, H H, Et H, H H, H                            1114 0 0 double bond carbonyl H, H H, Pr H, H H, H                            1115 1 0 double bond carbonyl H, H H, Pr H, H H, H                            1116 0 0 double bond carbonyl H, H Me, Me H, H H, H                           1117 1 0 double bond carbonyl H, H Me, Me H, H H, H                           1118 0 1 double bond carbonyl H, H H, Me H, H H, H                            1119 1 1 double bond carbonyl H, H H, Me H, H H, H                            1120 0 1 double bond carbonyl H, H H, Et H, H H, H                            1121 1 1 double bond carbonyl H, H H, Et H, H H, H                            1122 0 1 double bond carbonyl H, H H, Pr H, H H, H                            1123 1 1 double bond carbonyl H, H H, Pr H, H H, H                            1124 0 1 double bond carbonyl H, H Me, Me H, H H, H                           1125 1 1 double bond carbonyl H, H Me, Me H, H H, H                           1126 0 0 double bond carbonyl H, H Me, OH H, H H, H                           1127 1 0 double bond carbonyl H, H Me, OH H, H H, H                           1128 2 0 double bond carbonyl H, H Me, OH H, H H, H                           1129 0 1 double bond carbonyl H, H Me, OH H, H H, H                           1130 1 1 double bond carbonyl H, H Me, OH H, H H, H                           1131 2 1 double bond carbonyl H, H Me, OH H, H H, H                           1132 0 0 double bond carbonyl H, H Me, OAc H, H H, H                          1133 1 0 double bond carbonyl H, H Me, OAc H, H H, H                          1134 2 0 double bond carbonyl H, H Me, OAc H, H H, H                          1135 0 1 double bond carbonyl H, H Me, OAc H, H H, H                          1136 1 1 double bond carbonyl H, H Me, OAc H, H H, H                          1137 2 1 double bond carbonyl H, H Me, OAc H, H H, H                          1138 0 0 double bond carbonyl H, H Me, OCOn-Bu H, H H, H                      1139 1 0 double bond carbonyl H, H Me, OCOn-Bu H, H H, H                      1140 2 0 double bond carbonyl H, H Me, OCOn-Bu H, H H, H                      1141 0 1 double bond carbonyl H, H Me, OCOn-Bu H, H H, H                      1142 1 1 double bond carbonyl H, H Me, OCOn-Bu H, H H, H                      1143 2 1 double bond carbonyl H, H Me, OCOn-Bu H, H H, H                      1144 0 0 double bond carbonyl H, H Et, OH H, H H, H                           1145 1 0 double bond carbonyl H, H Et, OH H, H H, H                         __________________________________________________________________________

                                      TABLE 1-2                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B  X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                    __________________________________________________________________________    1146  0 1 double bond                                                                         carbonyl                                                                           H, H                                                                              Et, OH H, H                                                                              H, H                                        1147 1 1 double bond carbonyl H, H Et, OH H, H H, H                           1148 0 0 double bond carbonyl H, H Pr, OH H, H H, H                           1149 1 0 double bond carbonyl H, H Pr, OH H, H H, H                           1150 0 1 double bond carbonyl H, H Pr, OH H, H H, H                           1151 1 1 double bond carbonyl H, H Pr, OH H, H H, H                           1152 0 0 double bond carbonyl H, H CH.sub.2 Ph, OH H, H H, H                  1153 1 0 double bond carbonyl H, H CH.sub.2 Ph, OH H, H H, H                  1154 0 1 double bond carbonyl H, H CH.sub.2 Ph, OH H, H H, H                  1155 1 1 double bond carbonyl H, H CH.sub.2 Ph, OH H, H H, H                  1156 0 0 double bond carbonyl H, H Me, CH.sub.2 OH H, H H, H                  1157 1 0 double bond carbonyl H, H Me, CH.sub.2 OH H, H H, H                  1158 0 1 double bond carbonyl H, H Me, CH.sub.2 OH H, H H, H                  1159 1 1 double bond carbonyl H, H Me, CH.sub.2 OH H, H H, H                  1160 0 1 double bond carbonyl H, H H, OMe H, H H, H                           1161 1 1 double bond carbonyl H, H H, OMe H, H H, H                           1162 0 1 double bond carbonyl H, H H, OEt H, H H, H                           1163 1 1 double bond carbonyl H, H H, OEt H, H H, H                           1164 0 1 double bond carbonyl H, H H, SMe H, H H, H                           1165 1 1 double bond carbonyl H, H H, SMe H, H H, H                           1166 0 1 double bond carbonyl H, H H, tBu H, H H, H                           1167 1 1 double bond carbonyl H, H H, tBu H, H H, H                           1168 0 1 double bond carbonyl H, H H, allyl H, H H, H                         1169 1 1 double bond carbonyl H, H H, allyl H, H H, H                         1170 0 0 double bond carbonyl H, H H, H H, Me H, H                            1171 1 0 double bond carbonyl H, H H, H H, Me H, H                            1172 0 0 double bond carbonyl H, H H, H H, Et H, H                            1173 1 0 double bond carbonyl H, H H, H H, Et H, H                            1174 0 0 double bond carbonyl H, H H, H H, Pr H, H                            1175 1 0 double bond carbonyl H, H H, H H, Pr H, H                            1176 0 1 double bond carbonyl H, H H, H H, Me H, H                            1177 1 1 double bond carbonyl H, H H, H H, Me H, H                            1178 0 1 double bond carbonyl H, H H, H H, Et H, H                            1179 1 1 double bond carbonyl H, H H, H H, Et H, H                            1180 0 1 double bond carbonyl H, H H, H H, Pr H, H                            1181 1 1 double bond carbonyl H, H H, H H, Pr H, H                            1182 0 1 double bond carbonyl H, H H, H H, H H, Me                            1183 1 1 double bond carbonyl H, H H, H H, H H, Me                            1184 0 1 double bond carbonyl H, H H, H H, H H, Et                            1185 1 1 double bond carbonyl H, H H, H H, H H, Et                            1186 0 1 double bond carbonyl H, H H, H H, H H, tBu                           1187 1 1 double bond carbonyl H, H H, H H, H H, tBu                         __________________________________________________________________________

                                      TABLE 1-3                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B                                                                              X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                      __________________________________________________________________________    1201  0 0 H, H                                                                              carbonyl                                                                           H, H                                                                              H, H   H, H                                                                              H, H                                          1202 1 0 H, H carbonyl H, H H, H H, H H, H                                    1203 2 0 H, H carbonyl H, H H, H H, H H, H                                    1204 0 1 H, H carbonyl H, H H, H H, H H, H                                    1205 1 1 H, H carbonyl H, H H, H H, H H, H                                    1206 2 1 H, H carbonyl H, H H, H H, H H, H                                    1207 0 2 H, H carbonyl H, H H, H H, H H, H                                    1208 1 2 H, H carbonyl H, H H, H H, H H, H                                    1209 2 2 H, H carbonyl H, H H, H H, H H, H                                    1210 0 0 H, H carbonyl H, H H, Me H, H H, H                                   1211 1 0 H, H carbonyl H, H H, Me H, H H, H                                   1212 0 0 H, H carbonyl H, H H, Et H, H H, H                                   1213 1 0 H, H carbonyl H, H H, Et H, H H, H                                   1214 0 0 H, H carbonyl H, H H, Pr H, H H, H                                   1215 1 0 H, H carbonyl H, H H, Pr H, H H, H                                   1216 0 0 H, H carbonyl H, H Me, Me H, H H, H                                  1217 1 0 H, H carbonyl H, H Me, Me H, H H, H                                  1218 0 1 H, H carbonyl H, H H, Me H, H H, H                                   1219 1 1 H, H carbonyl H, H H, Me H, H H, H                                   1220 0 1 H, H carbonyl H, H H, Et H, H H, H                                   1221 1 1 H, H carbonyl H, H H, Et H, H H, H                                   1222 0 1 H, H carbonyl H, H H, Pr H, H H, H                                   1223 1 1 H, H carbonyl H, H H, Pr H, H H, H                                   1224 0 1 H, H carbonyl H, H Me, Me H, H H, H                                  1225 1 1 H, H carbonyl H, H Me, Me H, H H, H                                  1226 0 0 H, H carbonyl H, H Me, OH H, H H, H                                  1227 1 0 H, H carbonyl H, H Me, OH H, H H, H                                  1228 2 0 H, H carbonyl H, H Me, OH H, H H, H                                  1229 0 1 H, H carbonyl H, H Me, OH H, H H, H                                  1230 1 1 H, H carbonyl H, H Me, OH H, H H, H                                  1231 2 1 H, H carbonyl H, H Me, OH H, H H, H                                  1232 0 0 H, H carbonyl H, H Me, OAc H, H H, H                                 1233 1 0 H, H carbonyl H, H Me, OAc H, H H, H                                 1234 2 0 H, H carbonyl H, H Me, OAc H, H H, H                                 1235 0 1 H, H carbonyl H, H Me, OAc H, H H, H                                 1236 1 1 H, H carbonyl H, H Me, OAc H, H H, H                                 1237 2 1 H, H carbonyl H, H Me, OAc H, H H, H                                 1238 0 0 H, H carbonyl H, H Me, OCOn-Bu H, H H, H                             1239 1 0 H, H carbonyl H, H Me, OCOn-Bu H, H H, H                             1240 2 0 H, H carbonyl H, H Me, OCOn-Bu H, H H, H                             1241 0 1 H, H carbonyl H, H Me, OCOn-Bu H, H H, H                             1242 1 1 H, H carbonyl H, H Me, OCOn-Bu H, H H, H                             1243 2 1 H, H carbonyl H, H Me, OCOn-Bu H, H H, H                             1244 0 0 H, H carbonyl H, H Et, OH H, H H, H                                  1245 1 0 H, H carbonyl H, H Et, OH H, H H, H                                __________________________________________________________________________

                                      TABLE 1-4                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B                                                                              X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                      __________________________________________________________________________    1246  0 1 H, H                                                                              carbonyl                                                                           H, H                                                                              Et, OH H, H                                                                              H, H                                          1247 1 1 H, H carbonyl H, H Et, OH H, H H, H                                  1248 0 0 H, H carbonyl H, H Pr, OH H, H H, H                                  1249 1 0 H, H carbonyl H, H Pr, OH H, H H, H                                  1250 0 1 H, H carbonyl H, H Pr, OH H, H H, H                                  1251 1 1 H, H carbonyl H, H Pr, OH H, H H, H                                  1252 0 0 H, H carbonyl H, H CH.sub.2 Ph, OH H, H H, H                         1253 1 0 H, H carbonyl H, H CH.sub.2 Ph, OH H, H H, H                         1254 0 1 H, H carbonyl H, H CH.sub.2 Ph, OH H, H H, H                         1255 1 1 H, H carbonyl H, H CH.sub.2 Ph, OH H, H H, H                         1256 0 0 H, H carbonyl H, H Me, CH.sub.2 OH H, H H, H                         1257 1 0 H, H carbonyl H, H Me, CH.sub.2 OH H, H H, H                         1258 0 1 H, H carbonyl H, H Me, CH.sub.2 OH H, H H, H                         1259 1 1 H, H carbonyl H, H Me, CH.sub.2 OH H, H H, H                         1260 0 1 H, H carbonyl H, H H, OMe H, H H, H                                  1261 1 1 H, H carbonyl H, H H, OMe H, H H, H                                  1262 0 1 H, H carbonyl H, H H, OEt H, H H, H                                  1263 1 1 H, H carbonyl H, H H, OEt H, H H, H                                  1264 0 1 H, H carbonyl H, H H, SMe H, H H, H                                  1265 1 1 H, H carbonyl H, H H, SMe H, H H, H                                  1266 0 1 H, H carbonyl H, H H, tBu H, H H, H                                  1267 1 1 H, H carbonyl H, H H, tBu H, H H, H                                  1268 0 1 H, H carbonyl H, H H, allyl H, H H, H                                1269 1 1 H, H carbonyl H, H H, allyl H, H H, H                                1270 0 0 H, H carbonyl H, H H, H H, Me H, H                                   1271 1 0 H, H carbonyl H, H H, H H, Me H, H                                   1272 0 0 H, H carbonyl H, H H, H H, Et H, H                                   1273 1 0 H, H carbonyl H, H H, H H, Et H, H                                   1274 0 0 H, H carbonyl H, H H, H H, Pr H, H                                   1275 1 0 H, H carbonyl H, H H, H H, Pr H, H                                   1276 0 1 H, H carbonyl H, H H, H H, Me H, H                                   1277 1 1 H, H carbonyl H, H H, H H, Me H, H                                   1278 0 1 H, H carbonyl H, H H, H H, Et H, H                                   1279 1 1 H, H carbonyl H, H H, H H, Et H, H                                   1280 0 1 H, H carbonyl H, H H, H H, Pr H, H                                   1281 1 1 H, H carbonyl H, H H, H H, Pr H, H                                   1282 0 1 H, H carbonyl H, H H, H H, H H, Me                                   1283 1 1 H, H carbonyl H, H H, H H, H H, Me                                   1284 0 1 H, H carbonyl H, H H, H H, H H, Et                                   1285 1 1 H, H carbonyl H, H H, H H, H H, Et                                   1286 0 1 H, H carbonyl H, H H, H H, H H, tBu                                  1287 1 1 H, H carbonyl H, H H, H H, H H, tBu                                __________________________________________________________________________

                                      TABLE 1-5                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B    X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                  __________________________________________________________________________    1301  0 0 A = OH, B = H                                                                         carbonyl                                                                           H, H                                                                              H, H   H H H, H                                      1302 1 0 A = OH, B = H carbonyl H, H H, H H, H H, H                           1303 2 0 A = OH, B = H carbonyl H, H H, H H, H H, H                           1304 0 1 A = OH, B = H carbonyl H, H H, H H, H H, H                           1305 1 1 A = OH, B = H carbonyl H, H H, H H, H H, H                           1306 2 1 A = OH, B = H carbonyl H, H H, H H, H H, H                           1307 0 2 A = OH, B = H carbonyl H, H H, H H, H H, H                           1308 1 2 A = OH, B = H carbonyl H, H H, H H, H H, H                           1309 2 2 A = OH, B = H carbonyl H, H H, H H, H H, H                           1310 0 0 A = OH, B = H carbonyl H, H H, Me H, H H, H                          1311 1 0 A = OH, B = H carbonyl H, H H, Me H, H H, H                          1312 0 0 A = OH, B = H carbonyl H, H H, Et H, H H, H                          1313 1 0 A = OH, B = H carbonyl H, H H, Et H, H H, H                          1314 0 0 A = OH, B = H carbonyl H, H H, Pr H, H H, H                          1315 1 0 A = OH, B = H carbonyl H, H H, Pr H, H H, H                          1316 0 0 A = OH, B = H carbonyl H, H Me, Me H, H H, H                         1317 1 0 A = OH, B = H carbonyl H, H Me, Me H, H H, H                         1318 0 1 A = OH, B = H carbonyl H, H H, Me H, H H, H                          1319 1 1 A = OH, B = H carbonyl H, H H, Me H, H H, H                          1320 0 1 A = OH, B = H carbonyl H, H H, Et H, H H, H                          1321 1 1 A = OH, B = H carbonyl H, H H, Et H, H H, H                          1322 0 1 A = OH, B = H carbonyl H, H H, Pr H, H H, H                          1323 1 1 A = OH, B = H carbonyl H, H H, Pr H, H H, H                          1324 0 1 A = OH, B = H carbonyl H, H Me, Me H, H H, H                         1325 1 1 A = OH, B = H carbonyl H, H Me, Me H, H H, H                         1326 0 0 A = OH, B = H carbonyl H, H Me, OH H, H H, H                         1327 1 0 A = OH, B = H carbonyl H, H Me, OH H, H H, H                         1328 2 0 A = OH, B = H carbonyl H, H Me, OH H, H H, H                         1329 0 1 A = OH, B = H carbonyl H, H Me, OH H, H H, H                         1330 1 1 A = OH, B = H carbonyl H, H Me, OH H, H H, H                         1331 2 1 A = OH, B = H carbonyl H, H Me, OH H, H H, H                         1332 0 0 A = OH, B = H carbonyl H, H Me, OAc H, H H, H                        1333 1 0 A = OH, B = H carbonyl H, H Me, OAc H, H H, H                        1334 2 0 A = OH, B = H carbonyl H, H Me, OAc H, H H, H                        1335 0 1 A = OH, B = H carbonyl H, H Me, OAc H, H H, H                        1336 1 1 A = OH, B = H carbonyl H, H Me, OAc H, H H, H                        1337 2 1 A = OH, B = H carbonyl H, H Me, OAc H, H H, H                        1338 0 0 A = OH, B = H carbonyl H, H Me, OCOn-Bu H, H H, H                    1339 1 0 A = OH, B = H carbonyl H, H Me, OCOn-Bu H, H H, H                    1340 2 0 A = OH, B = H carbonyl H, H Me, OCOn-Bu H, H H, H                    1341 0 1 A = OH, B = H carbonyl H, H Me, OCOn-Bu H, H H, H                    1342 1 1 A = OH, B = H carbonyl H, H Me, OCOn-Bu H, H H, H                    1343 2 1 A = OH, B = H carbonyl H, H Me, OCOn-Bu H, H H, H                    1344 0 0 A = OH, B = H carbonyl H, H Et, OH H, H H, H                         1345 1 0 A = OH, B = H carbonyl H, H Et, OH H, H H, H                       __________________________________________________________________________

                                      TABLE 1-6                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B    X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                  __________________________________________________________________________    1346  0 1 A = OH, B = H                                                                         carbonyl                                                                           H, H                                                                              Et, OH H, H                                                                              H, H                                      1347 1 1 A = OH, B = H carbonyl H, H Et, OH H, H H, H                         1348 0 0 A = OH, B = H carbonyl H, H Pr, OH H, H H, H                         1349 1 0 A = OH, B = H carbonyl H, H Pr, OH H, H H, H                         1350 0 1 A = OH, B = H carbonyl H, H Pr, OH H, H H, H                         1351 1 1 A = OH, B = H carbonyl H, H Pr, OH H, H H, H                         1352 0 0 A = OH, B = H carbonyl H, H CH.sub.2 Ph, OH H, H H, H                1353 1 0 A = OH, B = H carbonyl H, H CH.sub.2 Ph, OH H, H H, H                1354 0 1 A = OH, B = H carbonyl H, H CH.sub.2 Ph, OH H, H H, H                1355 1 1 A = OH, B = H carbonyl H, H CH.sub.2 Ph, OH H, H H, H                1356 0 0 A = OH, B = H carbonyl H, H Me, CH.sub.2 OH H, H H, H                1357 1 0 A = OH, B = H carbonyl H, H Me, CH.sub.2 OH H, H H, H                1358 0 1 A = OH, B = H carbonyl H, H Me, CH.sub.2 OH H, H H, H                1359 1 1 A = OH, B = H carbonyl H, H Me, CH.sub.2 OH H, H H, H                1360 0 1 A = OH, B = H carbonyl H, H H, OMe H, H H, H                         1361 1 1 A = OH, B = H carbonyl H, H H, OMe H, H H, H                         1362 0 1 A = OH, B = H carbonyl H, H H, OEt H, H H, H                         1363 1 1 A = OH, B = H carbonyl H, H H, OEt H, H H, H                         1364 0 1 A = OH, B = H carbonyl H, H H, SMe H, H H, H                         1365 1 1 A = OH, B = H carbonyl H, H H, SMe H, H H, H                         1366 0 1 A = OH, B = H carbonyl H, H H, tBu H, H H, H                         1367 1 1 A = OH, B = H carbonyl H, H H, tBu H, H H, H                         1368 0 1 A = OH, B = H carbonyl H, H H, allyl H, H H, H                       1369 1 1 A = OH, B = H carbonyl H, H H, allyl H, H H, H                       1370 0 0 A = OH, B = H carbonyl H, H H, H H, Me H, H                          1371 1 0 A = OH, B = H carbonyl H, H H, H H, Me H, H                          1372 0 0 A = OH, B = H carbonyl H, H H, H H, Et H, H                          1373 1 0 A = OH, B = 4 carbonyl H, H H, H H, Et H, H                          1374 0 0 A = OH, B = H carbonyl H, H H, H H, Pr H, H                          1375 1 0 A = OH, B = H carbonyl H, H H, H H, Pr H, H                          1376 0 1 A = OH, B = H carbonyl H, H H, H H, Me H, H                          1377 1 1 A = OH, B = H carbonyl H, H H, H H, Me H, H                          1378 0 1 A = OH, B = H carbonyl H, H H, H H, Et H, H                          1379 1 1 A = OH, B = H carbonyl H, H H, H H, Et H, H                          1380 0 1 A = OH, B = H carbonyl H, H H, H H, Pr H, H                          1381 1 1 A = OH, B = H carbonyl H, H H, H H, Pr H, H                          1382 0 1 A = OH, B = H carbonyl H, H H, H H, H H, Me                          1383 1 1 A = OH, B = H carbonyl H, H H, H H, H H, Me                          1384 0 1 A = OH, B = H carbonyl H, H H, H H, H H, Et                          1385 1 1 A = OH, B = H carbonyl H, H H, H H, H H, Et                          1386 0 1 A = OH, B = H carbonyl H, H H, H H, H H, tBu                         1387 1 1 A = OH, B = H carbonyl H, H H, H H, H H, tBu                       __________________________________________________________________________

                                      TABLE 1-7                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No                                                                            n m A, B  X, Y                                                                              R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                     __________________________________________________________________________    1401  0 0 double bond                                                                         OH, H                                                                             H, H                                                                              H, H   H, H                                                                              H, H                                         1402 1 0 double bond OH, H H, H H, H H, H H, H                                1403 2 0 double bond OH, H H, H H, H H, H H, H                                1404 0 1 double bond OH, H H, H H, H H, H H, H                                1405 1 1 double bond OH, H H, H H, H H, H H, H                                1406 2 1 double bond OH, H H, H H, H H, H H, H                                1407 0 2 double bond OH, H H, H H, H H, H H, H                                1408 1 2 double bond OH, H H, H H, H H, H H, H                                1409 2 2 double bond OH, H H, H H, H H, H H, H                                1410 0 0 double bond OH, H H, H H, Me H, H H, H                               1411 1 0 double bond OH, H H, H H, Me H, H H, H                               1412 0 0 double bond OH, H H, H H, Et H, H H, H                               1413 1 0 double bond OH, H H, H H, Et H, H H, H                               1414 0 0 double bond OH, H H, H H, Pr H, H H, H                               1415 1 0 double bond OH, H H, H H, Pr H, H H, H                               1416 0 0 double bond OH, H H, H Me, Me H, H H, H                              1417 1 0 double bond OH, H H, H Me, Me H, H H, H                              1418 0 1 double bond OH, H H, H H, Me H, H H, H                               1419 1 1 double bond OH, H H, H H, Me H, H H, H                               1420 0 1 double bond OH, H H, H H, Et H, H H, H                               1421 1 1 double bond OH, H H, H H, Et H, H H, H                               1422 0 1 double bond OH, H H, H H, Pr H, H H, H                               1423 1 1 double bond OH, H H, H H, Pr H, H H, H                               1424 0 1 double bond OH, H H, H Me, Me H, H H, H                              1425 1 1 double bond OH, H H, H Me, Me H, H H, H                              1426 0 0 double bond OH, H H, H Me, OH H, H H, H                              1427 1 0 double bond OH, H H, H Me, OH H, H H, H                              1428 2 0 double bond OH, H H, H Me, OH H, H H, H                              1429 0 1 double bond OH, H H, H Me, OH H, H H, H                              1430 1 1 double bond OH, H H, H Me, OH H, H H, H                              1431 2 1 double bond OH, H H, H Me, OH H, H H, H                              1432 0 0 double bond OH, H H, H Me, OAc H, H H, H                             1433 1 0 double bond OH, H H, H Me, OAc H, H H, H                             1434 2 0 double bond OH, H H, H Me, OAc H, H H, H                             1435 0 1 double bond OH, H H, H Me, OAc H, H H, H                             1436 1 1 double bond OH, H H, H Me, OAc H, H H, H                             1437 2 1 double bond OH, H H, H Me, OAc H, H H, H                             1438 0 0 double bond OH, H H, H Me, OCOn-Bu H, H H, H                         1439 1 0 double bond OH, H H, H Me, OCOn-Bu H, H H, H                         1440 2 0 double bond OH, H H, H Me, OCOn-Bu H, H H, H                         1441 0 1 double bond OH, H H, H Me, OCOn-Bu H, H H, H                         1442 1 1 double bond OH, H H, H Me, OCOn-Bu H, H H, H                         1443 2 1 double bond OH, H H, H Me, OCOn-Bu H, H H, H                         1444 0 0 double bond OH, H H, H Et, OH H, H H, H                              1445 1 0 double bond OH, H H, H Et, OH H, H H, H                            __________________________________________________________________________

                                      TABLE 1-8                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No                                                                            n m A, B  X, Y                                                                              R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                     __________________________________________________________________________    1446  0 1 double bond                                                                         OH, H                                                                             H, H                                                                              Et, OH H, H                                                                              H, H                                         1447 1 1 double bond OH, H H, H Et, OH H, H H, H                              1448 0 0 double bond OH, H H, H Pr, OH H, H H, H                              1449 1 0 double bond OH, H H, H Pr, OH H, H H, H                              1450 0 1 double bond OH, H H, H Pr, OH H, H H, H                              1451 1 1 double bond OH, H H, H Pr, OH H, H H, H                              1452 0 0 double bond OH, H H, H CH.sub.2 Ph, OH H, H H, H                     1453 1 0 double bond OH, H H, H CH.sub.2 Ph, OH H, H H, H                     1454 0 1 double bond OH, H H, H CH.sub.2 Ph, OH H, H H, H                     1455 1 1 double bond OH, H H, H CH.sub.2 Ph, OH H, H H, H                     1456 0 0 double bond OH, H H, H Me, CH.sub.2 OH H, H H, H                     1457 1 0 double bond OH, H H, H Me, CH.sub.2 OH H, H H, H                     1458 0 1 double bond OH, H H, H Me, CH.sub.2 OH H, H H, H                     1459 1 1 double bond OH, H H, H Me, CH.sub.2 OH H, H H, H                     1460 0 1 double bond OH, H H, H H, OMe H, H H, H                              1461 1 1 double bond OH, H H, H H, OMe H, H H, H                              1462 0 1 double bond OH, H H, H H, OEt H, H H, H                              1463 1 1 double bond OH, H H, H H, OEt H, H H, H                              1464 0 1 double bond OH, H H, H H, SMe H, H H, H                              1465 1 1 double bond OH, H H, H H, SMe H, H H, H                              1466 0 1 double bond OH, H H, H H, tBu H, H H, H                              1467 1 1 double bond OH, H H, H H, tBu H, H H, H                              1468 0 1 double bond OH, H H, H H, allyl H, H H, H                            1469 1 1 double bond OH, H H, H H, allyl H, H H, H                            1470 0 0 double bond OH, H H, H H, H H, Me H, H                               1471 1 0 double bond OH, H H, H H, H H, Me H, H                               1472 0 0 double bond OH, H H, H H, H H, Et H, H                               1473 1 0 double bond OH, H H, H H, H H, Et H, H                               1474 0 0 double bond OH, H H, H H, H H, Pr H, H                               1475 1 0 double bond OH, H H, H H, H H, Pr H, H                               1476 0 1 double bond OH, H H, H H, H H, Me H, H                               1477 1 1 double bond OH, H H, H H, H H, Me H, H                               1478 0 1 double bond OH, H H, H H, H H, Et H, H                               1479 1 1 double bond OH, H H, H H, H H, Et H, H                               1480 0 1 double bond OH, H H, H H, H H, Pr H, H                               1481 1 1 double bond OH, H H, H H, H H, Pr H, H                               1482 0 1 double bond OH, H H, H H, H H, H H, Me                               1483 1 1 double bond OH, H H, H H, H H, H H, Me                               1484 0 1 double bond OH, H H, H H, H H, H H, Et                               1485 1 1 double bond OH, H H, H H, H H, H H, Et                               1486 0 1 double bond OH, H H, H H, H H, H H, tBu                              1487 1 1 double bond OH, H H, H H, H H, H H, tBu                            __________________________________________________________________________

                                      TABLE 1-9                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B                                                                             X, Y                                                                              R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                        __________________________________________________________________________    1501  0 0 H, H                                                                             OH, H                                                                             H, H                                                                              H, H   H, H                                                                              H, H                                            1502 1 0 H, H OH, H H, H H, H H, H H, H                                       1503 2 0 H, H OH, H H, H H, H H, H H, H                                       1504 0 1 H, H OH, H H, H H, H H, H H, H                                       1505 1 1 H, H OH, H H, H H, H H, H H, H                                       1506 2 1 H, H OH, H H, H H, H H, H H, H                                       1507 0 2 H, H OH, H H, H H, H H, H H, H                                       1508 1 2 H, H OH, H H, H H, H H, H H, H                                       1509 2 2 H, H OH, H H, H H, H H, H H, H                                       1510 0 0 H, H OH, H H, H H, Me H, H H, H                                      1511 1 0 H, H OH, H H, H H, Me H, H H, H                                      1512 0 0 H, H OH, H H, H H, Et H, H H, H                                      1513 1 0 H, H OH, H H, H H, Et H, H H, H                                      1514 0 0 H, H OH, H H, H H, Pr H, H H, H                                      1515 1 0 H, H OH, H H, H H, Pr H, H H, H                                      1516 0 0 H, H OH, H H, H Me, Me H, H H, H                                     1517 1 0 H, H OH, H H, H Me, Me H, H H, H                                     1518 0 1 H, H OH, H H, H H, Me H, H H, H                                      1519 1 1 H, H OH, H H, H H, Me H, H H, H                                      1520 0 1 H, H OH, H H, H H, Et H, H H, H                                      1521 1 1 H, H OH, H H, H H, Et H, H H, H                                      1522 0 1 H, H OH, H H, H H, Pr H, H H, H                                      1523 1 1 H, H OH, H H, H H, Pr H, H H, H                                      1524 0 1 H, H OH, H H, H Me, Me H, H H, H                                     1525 1 1 H, H OH, H H, H Me, Me H, H H, H                                     1526 0 0 H, H OH, H H, H Me, OH H, H H, H                                     1527 1 0 H, H OH, H H, H Me, OH H, H H, H                                     1528 2 0 H, H OH, H H, H Me, OH H, H H, H                                     1529 0 1 H, H OH, H H, H Me, OH H, H H, H                                     1530 1 1 H, H OH, H H, H Me, OH H, H H, H                                     1531 2 1 H, H OH, H H, H Me, OH H, H H, H                                     1532 0 0 H, H OH, H H, H Me, OAc H, H H, H                                    1533 1 0 H, H OH, H H, H Me, OAc H, H H, H                                    1534 2 0 H, H OH, H H, H Me, OAc H, H H, H                                    1535 0 1 H, H OH, H H, H Me, OAc H, H H, H                                    1536 1 1 H, H OH, H H, H Me, OAc H, H H, H                                    1537 2 1 H, H OH, H H, H Me, OAc H, H H, H                                    1538 0 0 H, H OH, H H, H Me, OCOn-Bu H, H H, H                                1539 1 0 H, H OH, H H, H Me, OCOn-Bu H, H H, H                                1540 2 0 H, H OH, H H, H Me, OCOn-Bu H, H H, H                                1541 0 1 H, H OH, H H, H Me, OCOn-Bu H, H H, H                                1542 1 1 H, H OH, H H, H Me, OCOn-Bu H, H H, H                                1543 2 1 H, H OH, H H, H Me, OCOn-Bu H, H H, H                                1544 0 0 H, H OH, H H, H Et, OH H, H H, H                                     1545 1 0 H, H OH, H H, H Et, OH H, H H, H                                   __________________________________________________________________________

                                      TABLE 1-10                                  __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B                                                                             X, Y                                                                              R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                        __________________________________________________________________________    1546  0 1 H, H                                                                             OH, H                                                                             H, H                                                                              Et, OH H, H                                                                              H, H                                            1547 1 1 H, H OH, H H, H Et, OH H, H H, H                                     1548 0 0 H, H OH, H H, H Pr, OH H, H H, H                                     1549 1 0 H, H OH, H H, H Pr, OH H, H H, H                                     1550 0 1 H, H OH, H H, H Pr, OH H, H H, H                                     1551 1 1 H, H OH, H H, H Pr, OH H, H H, H                                     1552 0 0 H, H OH, H H, H CH.sub.2 Ph, OH H, H H, H                            1553 1 0 H, H OH, H H, H CH.sub.2 Ph, OH H, H H, H                            1554 0 1 H, H OH, H H, H CH.sub.2 Ph, OH H, H H, H                            1555 1 1 H, H OH, H H, H CH.sub.2 Ph, OH H, H H, H                            1556 0 0 H, H OH, H H, H Me, CH.sub.2 OH H, H H, H                            1557 1 0 H, H OH, H H, H Me, CH.sub.2 OH H, H H, H                            1558 0 1 H, H OH, H H, H Me, CH.sub.2 OH H, H H, H                            1559 1 1 H, H OH, H H, H Me, CH.sub.2 OH H, H H, H                            1560 0 1 H, H OH, H H, H H, OMe H, H H, H                                     1561 1 1 H, H OH, H H, H H, OMe H, H H, H                                     1562 0 1 H, H OH, H H, H H, OEt H, H H, H                                     1563 1 1 H, H OH, H H, H H, OEt H, H H, H                                     1564 0 1 H, H OH, H H, H H, SMe H, H H, H                                     1565 1 1 H, H OH, H H, H H, SMe H, H H, H                                     1566 0 1 H, H OH, H H, H H, tBu H, H H, H                                     1567 1 1 H, H OH, H H, H H, tBu H, H H, H                                     1568 0 1 H, H OH, H H, H H, allyl H, H H, H                                   1569 1 1 H, H OH, H H, H H, allyl H, H H, H                                   1570 0 0 H, H OH, H H, H H, H H, H H, H                                       1571 1 0 H, H OH, H H, H H, H H, Me H, H                                      1572 0 0 H, H OH, H H, H H, H H, Et H, H                                      1573 1 0 H, H OH, H H, H H, H H, Et H, H                                      1574 0 0 H, H OH, H H, H H, H H, Pr H, H                                      1575 1 0 H, H OH, H H, H H, H H, Pr H, H                                      1576 0 1 H, H OH, H H, H H, H H, Me H, H                                      1577 1 1 H, H OH, H H, H H, H H, Me H, H                                      1578 0 1 H, H OH, H H, H H, H H, Et H, H                                      1579 1 1 H, H OH, H H, H H, H H, Et H, H                                      1580 0 1 H, H OH, H H, H H, H H, Pr H, H                                      1581 1 1 H, H OH, H H, H H, H H, Pr H, H                                      1582 0 1 H, H OH, H H, H H, H H, H H, Me                                      1583 1 1 H, H OH, H H, H H, H H, H H, Me                                      1584 0 1 H, H OH, H H, H H, H H, H H, Et                                      1585 1 1 H, H OH, H H, H H, H H, H H, Et                                      1586 0 1 H, H OH, H H, H H, H H, H H, tBu                                     1587 1 1 H, H OH, H H, H H, H H, H H, tBu                                   __________________________________________________________________________

                                      TABLE 1-11                                  __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B    X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                  __________________________________________________________________________    1601  0 0 A = H, B = OH                                                                         carbonyl                                                                           H, H                                                                              H, H   H, H                                                                              H, H                                      1602 1 0 A = H, B = OH carbonyl H, H H, H H, H H, H                           1603 2 0 A = H, B = OH carbonyl H, H H, H H, H H, H                           1604 0 1 A = H, B = OH carbonyl H, H H, H H, H H, H                           1605 1 1 A = H, B = OH carbonyl H, H H, H H, H H, H                           1606 2 1 A = H, B = OH carbonyl H, H H, H H, H H, H                           1607 0 2 A = H, B = OH carbonyl H, H H, H H, H H, H                           1608 1 2 A = H, B = OH carbonyl H, H H, H H, H H, H                           1609 2 2 A = H, B = OH carbonyl H, H H, H H, H H, H                           1610 0 0 A = H, B = OH carbonyl H, H H, Me H, H H, H                          1611 1 0 A = H, B = OH carbonyl H, H H, Me H, H H, H                          1612 0 0 A = H, B = OH carbonyl H, H H, Et H, H H, H                          1613 1 0 A = H, B = OH carbonyl H, H H, Et H, H H, H                          1614 0 0 A = H, B = OH carbonyl H, H H, Pr H, H H, H                          1615 1 0 A = H, B = OH carbonyl H, H H, Pr H, H H, H                          1616 0 0 A = H, B = OH carbonyl H, H Me, Me H, H H, H                         1617 1 0 A = H, B = OH carbonyl H, H Me, Me H, H H, H                         1618 0 1 A = H, B = OH carbonyl H, H H, Me H, H H, H                          1619 1 1 A = H, B = OH carbonyl H, H H, Me H, H H, H                          1620 0 1 A = H, B = OH carbonyl H, H H, Et H, H H, H                          1621 1 1 A = H, B = OH carbonyl H, H H, Et H, H H, H                          1622 0 1 A = H, B = OH carbonyl H, H H, Pr H, H H, H                          1623 1 1 A = H, B = OH carbonyl H, H H, Pr H, H H, H                          1624 0 1 A = H, B = OH carbonyl H, H Me, Me H, H H, H                         1625 1 1 A = H, B = OH carbonyl H, H Me, Me H, H H, H                         1626 0 0 A = H, B = OH carbonyl H, H Me, OH H, H H, H                         1627 1 0 A = H, B = OH carbonyl H, H Me, OH H, H H, H                         1628 2 0 A = H, B = OH carbonyl H, H Me, OH H, H H, H                         1629 0 1 A = H, B = OH carbonyl H, H Me, OH H, H H, H                         1630 1 1 A = H, B = OH carbonyl H, H Me, OH H, H H, H                         1631 2 1 A = H, B = OH carbonyl H, H Me, OH H, H H, H                         1632 0 0 A = H, B = OH carbonyl H, H Me, OAc H, H H, H                        1633 1 0 A = H, B = OH carbonyl H, H Me, OAc H, H H, H                        1634 2 0 A = H, B = OH carbonyl H, H Me, OAc H, H H, H                        1635 0 1 A = H, B = OH carbonyl H, H Me, OAc H, H H, H                        1636 1 1 A = H, B = OH carbonyl H, H Me, OAc H, H H, H                        1637 2 1 A = H, B = OH carbonyl H, H Me, OAc H, H H, H                        1638 0 0 A = H, B = OH carbonyl H, H Me, OCOn-Bu H, H H, H                    1639 1 0 A = H, B = OH carbonyl H, H Me, OCOn-Bu H, H H, H                    1640 2 0 A = H, B = OH carbonyl H, H Me, OCOn-Bu H, H H, H                    1641 0 1 A = H, B = OH carbonyl H, H Me, OCOn-Bu H, H H, H                    1642 1 1 A = H, B = OH carbonyl H, H Me, OCOn-Bu H, H H, H                    1643 2 1 A = H, B = OH carbonyl H, H Me, OCOn-Bu H, H H, H                    1644 0 0 A = H, B = OH carbonyl H, H Et, OH H, H H, H                         1645 1 0 A = H, B = OH carbonyl H, H Et, OH H, H H, H                       __________________________________________________________________________

                                      TABLE 1-12                                  __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B    X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                  __________________________________________________________________________    1646  0 1 A = H, B = OH                                                                         carbonyl                                                                           H, H                                                                              Et, OH H, H                                                                              H, H                                      1647 1 1 A = H, B = OH carbonyl H, H Et, OH H, H H, H                         1648 0 0 A = H, B = OH carbonyl H, H Pr, OH H, H H, H                         1649 1 0 A = H, B = OH carbonyl H, H Pr, OH H, H H, H                         1650 0 1 A = H, B = OH carbonyl H, H Pr, OH H, H H, H                         1651 1 1 A = H, B = OH carbonyl H, H Pr, OH H, H H, H                         1652 0 0 A = H, B = OH carbonyl H, H CH.sub.2 Ph, OH H, H H, H                1653 1 0 A = H, B = OH carbonyl H, H CH.sub.2 Ph, OH H, H H, H                1654 0 1 A = H, B = OH carbonyl H, H CH.sub.2 Ph, OH H, H H, H                1655 1 1 A = H, B = OH carbonyl H, H CH.sub.2 Ph, OH H, H H, H                1656 0 0 A = H, B = OH carbonyl H, H Me, CH.sub.2 OH H, H H, H                1657 1 0 A = H, B = OH carbonyl H, H Me, CH.sub.2 OH H, H H, H                1658 0 1 A = H, B = OH carbonyl H, H Me, CH.sub.2 OH H, H H, H                1659 1 1 A = H, B = OH carbonyl H, H Me, CH.sub.2 OH H, H H, H                1660 0 1 A = H, B = OH carbonyl H, H H, OMe H, H H, H                         1661 1 1 A = H, B = OH carbonyl H, H H, OMe H, H H, H                         1662 0 1 A = H, B = OH carbonyl H, H H, OEt H, H H, H                         1663 1 1 A = H, B = OH carbonyl H, H H, OEt H, H H, H                         1664 0 1 A = H, B = OH carbonyl H, H H, SMe H, H H, H                         1665 1 1 A = H, B = OH carbonyl H, H H, SMe H, H H, H                         1666 0 1 A = H, B = OH carbonyl H, H H, tBu H, H H, H                         1667 1 1 A = H, B = OH carbonyl H, H H, tBu H, H H, H                         1668 0 1 A = H, B = OH carbonyl H, H H, allyl H, H H, H                       1669 1 1 A = H, B = OH carbonyl H, H H, allyl H, H H, H                       1670 0 0 A = H, B = OH carbonyl H, H H, H H, Me H, H                          1671 1 0 A = H, B = OH carbonyl H, H H, H H, Me H, H                          1672 0 0 A = H, B = OH carbonyl H, H H, H H, Et H, H                          1673 1 0 A = H, B = OH carbonyl H, H H, H H, Et H, H                          1674 0 0 A = H, B = OH carbonyl H, H H, H H, Pr H, H                          1675 1 0 A = H, B = OH carbonyl H, H H, H H, Pr H, H                          1676 0 1 A = H, B = OH carbonyl H, H H, H H, Me H, H                          1677 1 1 A = H, B = OH carbonyl H, H H, H H, Me H, H                          1678 0 1 A = H, B = OH carbonyl H, H H, H H, Et H, H                          1679 1 1 A = H, B = OH carbonyl H, H H, H H, Et H, H                          1680 0 1 A = H, B = OH carbonyl H, H H, H H Pr H, H                           1681 1 1 A = H, B = OH carbonyl H, H H, H H, Pr H, H                          1682 0 1 A = H, B = OH carbonyl H, H H, H H, H H, Me                          1683 1 1 A = H, B = OH carbonyl H, H H, H H, H H, Me                          1684 0 1 A = H, B = OH carbonyl H, H H, H H, H H, Et                          1685 1 1 A = H, B = OH carbonyl H, H H, H H, H H, Et                          1686 0 1 A = H, B = OH carbonyl H, H H, H H, H H, tBu                         1687 1 1 A = H, B = OH carbonyl H, H H, H H, H H, tBu                       __________________________________________________________________________

                                      TABLE 1-13                                  __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B    X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                  __________________________________________________________________________    1701  0 0 A = OH, B = H                                                                         OH, H                                                                              H, H                                                                              H, H   H, H                                                                              H, H                                      1702 1 0 A = OH, B = H OH, H H, H H, H H, H H, H                              1703 2 0 A = OH, B = H OH, H H, H H, H H, H H, H                              1704 0 1 A = OH, B = H OH, H H, H H, H H, H H, H                              1705 1 1 A = OH, B = H OH, H H, H H, H H, H H, H                              1706 2 1 A = OH, B = H OH, H H, H H, H H, H H, H                              1707 0 2 A = OH, B = H OH, H H, H H, H H, H H, H                              1708 1 2 A = OH, B = H OH, H H, H H, H H, H H, H                              1709 2 2 A = OH, B = H OH, H H, H H, H H, H H, H                              1710 0 0 A = OH, B = H OH, H H, H H, Me H, H H, H                             1711 1 0 A = OH, B = H OH, H H, H H, Me H, H H, H                             1712 0 0 A = OH, B = H OH, H H, H H, Et H, H H, H                             1713 1 0 A = OH, B = H OH, H H, H H, Et H, H H, H                             1714 0 0 A = OH, B = H OH, H H, H H, Pr H, H H, H                             1715 1 0 A = OH, B = H OH, H H, H H, Pr H, H H, H                             1716 0 0 A = OH, B = H OH, H H, H Me, Me H, H H, H                            1717 1 0 A = OH, B = H OH, H H, H Me, Me H, H H, H                            1718 0 1 A = OH, B = H OH, H H, H H, Me H, H H, H                             1719 1 1 A = OH, B = H OH, H H, H H, Me H, H H, H                             1720 0 1 A = OH, B = H OH, H H, H H, Et H, H H, H                             1721 1 1 A = OH, B = H OH, H H, H H, Et H, H H, H                             1722 0 1 A = OH, B = H OH, H H, H H, Pr H, H H, H                             1723 1 1 A = OH, B = H OH, H H, H H, Pr H, H H, H                             1724 0 1 A = OH, B = H OH, H H, H Me, Me H, H H, H                            1725 1 1 A = OH, B = H OH, H H, H Me, Me H, H H, H                            1726 0 0 A = OH, B = H OH, H H, H Me, OH H, H H, H                            1727 1 0 A = OH, B = H OH, H H, H Me, OH H, H H, H                            1728 2 0 A = OH, B = H OH, H H, H Me, OH H, H H, H                            1729 0 1 A = OH, B = H OH, H H, H Me, 0H H, H H, H                            1730 1 1 A = OH, B = H OH, H H, H Me, OH H, H H, H                            1731 2 1 A = OH, B = H OH, H H, H Me, OH H, H H, H                            1732 0 0 A = OH, B = H OH, H H, H Me, OAc H, H H, H                           1733 1 0 A = OH, B = H OH, H H, H Me, OAc H, H H, H                           1734 2 0 A = OH, B = H OH, H H, H Me, OAc H, H H, H                           1735 0 1 A = OH, B = H OH, H H, H Me, OAc H, H H, H                           1736 1 1 A = OH, B = H OH, H H, H Me, OAc H, H H, H                           1737 2 1 A = OH, B = H OH, H H, H Me, OAc H, H H, H                           1738 0 0 A = OH, B = H OH, H H, H Me, OCOn-Bu H, H H, H                       1739 1 0 A = OH, B = H OH, H H, H Me, OCOn-Bu H, H H, H                       1740 2 0 A = OH, B = H OH, H H, H Me, OCOn-Bu H, H H, H                       1741 0 1 A = OH, B = H OH, H H, H Me, OCOn-Bu H, H H, H                       1742 1 1 A = OH, B = H OH, H H, H Me, OCOn-Bu H, H H, H                       1743 2 1 A = OH, B = H OH, H H, H Me, OCOn-Bu H, H H, H                       1744 0 0 A = OH, B = H OH, H H, H Et, OH H, H H, H                            1745 1 0 A = OH, B = H OH, H H, H Et, OH H, H H, H                          __________________________________________________________________________

                                      TABLE 1-14                                  __________________________________________________________________________    Structure of Compound: formula [1], Z = [1a]                                  Comp. No.                                                                           n m A, B    X, Y R1, R2                                                                            R3, R4 R5, R6                                                                            R7, R8                                  __________________________________________________________________________    1746  0 1 A = OH, B = H                                                                         OH, H                                                                              H, H                                                                              Et, OH H, H                                                                              H, H                                      1747 1 1 A = OH, B = H OH, H H, H Et, OH H, H H, H                            1748 0 0 A = OH, B = H OH, H H, H Pr, OH H, H H, H                            1749 1 0 A = OH, B = H OH, H H, H Pr, OH H, H H, H                            1750 0 1 A = OH, B = H OH, H H, H Pr, OH H, H H, H                            1751 1 1 A = OH, B = H OH, H H, H Pr, OH H, H H, H                            1752 0 0 A = OH, B = H OH, H H, H CH.sub.2 Ph, OH H, H H, H                   1753 1 0 A = OH, B = H OH, H H, H CH.sub.2 Ph, OH H, H H, H                   1754 0 1 A = OH, B = H OH, H H, H CH.sub.2 Ph, OH H, H H, H                   1755 1 1 A = OH, B = H OH, H H, H CH.sub.2 Ph, OH H, H H, H                   1756 0 0 A = OH, B = H OH, H H, H Me, CH.sub.2 OH H, H H, H                   1757 1 0 A = OH, B = H OH, H H, H Me, CH.sub.2 OH H, H H, H                   1758 0 1 A = OH, B = H OH, H H, H Me, CH.sub.2 OH H, H H, H                   1759 1 1 A = OH, B = H OH, H H, H Me, CH.sub.2 OH H, H H, H                   1760 0 1 A = OH, B = H OH, H H, H H, OMe H, H H, H                            1761 1 1 A = OH, B = H OH, H H, H H, OMe H, H H, H                            1762 0 1 A = OH, B = H OH, H H, H H, OEt H, H H, H                            1763 1 1 A = OH, B = H OH, H H, H H, OEt H, H H, H                            1764 0 1 A = OH, B = H OH, H H, H H, SMe H, H H, H                            1765 1 1 A = OH, B = H OH, H H, H H, SMe H, H H, H                            1766 0 1 A = OH, B = H OH, H H, H H, tBu H, H H, H                            1767 1 1 A = OH, B = H OH, H H, H H, tBu H, H H, H                            1768 0 1 A = OH, B = H OH, H H, H H, allyl H, H H, H                          1769 1 1 A = OH, B = H OH, H H, H H, allyl H, H H, H                          1770 0 0 A = OH, B = H OH, H H, H H, H H, Me H, H                             1771 1 0 A = OH, B = H OH, H H, H H, H H, Me H, H                             1772 0 0 A = OH, B = H OH, H H, H H, H H, Et H, H                             1773 1 0 A = OH, B = H OH, H H, H H, H H, Et H, H                             1774 0 0 A = OH, B = H OH, H H, H H, H H, Pr H, H                             1775 1 0 A = OH, B = H OH, H H, H H, H H, Pr H, H                             1776 0 1 A = OH, B = H OH, H H, H H, H H, Me H, H                             1777 1 1 A = OH, B = H OH, H H, H H, H H, Me H, H                             1778 0 1 A = OH, B = H OH, H H, H H, H H, Et H, H                             1779 1 1 A = OH, B = H OH, H H, H H, H H, Et H, H                             1780 0 1 A = OH, B = H OH, H H, H H, H H, Pr H, H                             1781 1 1 A = OH, B = H OH, H H, H H, H H, Pr H, H                             1782 0 1 A = OH, B = H OH, H H, H H, H H, H H, Me                             1783 1 1 A = OH, B = H OH, H H, H H, H H, H H, Me                             1784 0 1 A = OH, B = H OH, H H, H H, H H, H H, Et                             1785 1 1 A = OH, B = H OH, H H, H H, H H, H H, Et                             1786 0 1 A = OH, B = H OH, H H, H H, H H, H H, tBu                            1787 1 1 A = OH, B = H OH, H H, H H, H H, H H, tBu                          __________________________________________________________________________

                                      TABLE 2-1                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1b]                                  Comp. No                                                                            n m A, B  X, Y R1, R2                                                                            R7, R8                                                                            R9  R10                                          __________________________________________________________________________    2101  0 0 double bond                                                                         carbonyl                                                                           H, H                                                                              H, H                                                                              H   H                                              2102 1 0 double bond carbonyl H, H H, H H H                                   2103 2 0 double bond carbonyl H, H H, H H H                                   2104 0 0 double bond carbonyl H, H H, H Me H                                  2105 1 0 double bond carbonyl H, H H, H Me H                                  2106 2 0 double bond carbonyl H, H H, H Me H                                  2107 0 0 double bond carbonyl H, H H, H Pentyl H                              2108 1 0 double bond carbonyl H, H H, H Pentyl H                              2109 2 0 double bond carbonyl H, H H, H Pentyl H                              2110 0 0 double bond carbonyl H, H H, H H Me                                  2111 1 0 double bond carbonyl H, H H, H H Me                                  2112 2 0 double bond carbonyl H, H H, H H Me                                  2113 0 0 double bond carbonyl H, H H, H Me Me                                 2114 1 0 double bond carbonyl H, H H, H Me Me                                 2115 2 0 double bond carbonyl H, H H, H Me Me                                 2116 0 0 double bond carbonyl H, H Me, Me H H                                 2117 1 0 double bond carbonyl H, H Me, Me H H                                 2118 2 0 double bond carbonyl H, H Me, Me H H                                 2119 0 0 double bond carbonyl H, H H, H H OMe                                 2120 1 0 double bond carbonyl H, H H, H H OMe                                 2121 2 0 double bond carbonyl H, H H, H H OMe                                 2122 0 0 double bond carbonyl H, H H, H H OEt                                 2123 1 0 double bond carbonyl H, H H, H H OEt                                 2124 2 0 double bond carbonyl H, H H, H H OEt                                 2125 0 1 double bond carbonyl H, H H, H H H                                   2126 1 1 double bond carbonyl H, H H, H H H                                   2127 2 1 double bond carbonyl H, H H, H H H                                   2128 0 1 double bond carbonyl H, H H, H H Me                                  2129 1 1 double bond carbonyl H, H H, H H Me                                  2130 2 1 double bond carbonyl H, H H, H H Me                                  2131 0 1 double bond carbonyl H, H Me, Me H H                                 2132 1 1 double bond carbonyl H, H Me, Me H H                                 2133 2 1 double bond carbonyl H, H Me, Me H H                                 2134 0 1 double bond carbonyl H, H Me, Me Me H                                2135 1 1 double bond carbonyl H, H Me, Me Me H                                2136 2 1 double bond carbonyl H, H Me, Me Me H                                2137 0 1 dduble bond carbonyl H, H H, H H OEt                                 2138 1 1 double bond carbonyl H, H H, H H OEt                                 2139 2 1 double bond carbonyl H, H H, H H OEt                                 2140 0 2 double bond carbonyl H, H H, H H H                                   2141 1 2 double bond carbonyl H, H H, H H H                                   2142 2 2 double bond carbonyl H, H H, H H H                                 __________________________________________________________________________

                                      TABLE 2-2                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1b]                                  Comp. No.                                                                           n m A, B    X, Y R1, R2                                                                            R7, R8 R9  R10                                     __________________________________________________________________________    2201  0 0 A = OH, B = H                                                                         carbonyl                                                                           H, H                                                                              H, H   H   H                                         2202 1 0 A = OH, B = H carbonyl H, H H, H H H                                 2203 2 0 A = OH, B = H carbonyl H, H H, H H H                                 2204 0 0 A = OH, B = H carbonyl H, H H, H H H                                 2205 1 0 A = OH, B = H carbonyl H, H H, H H H                                 2206 2 0 A = OH, B = H carbonyl H, H H, H H H                                 2207 0 0 A = OH, B = H carbonyl H, H H, H Pentyl H                            2208 1 0 A = OH, B = H carbonyl H, H H, H Pentyl H                            2209 2 0 A = OH, B = H carbonyl H, H H, H Pentyl H                            2210 0 0 A = OH, B = H carbonyl H, H H, H Me H                                2211 1 0 A = OH, B = H carbonyl H, H H, H Me H                                2212 2 0 A = OH, B = H carbonyl H, H H, H Me H                                2213 0 0 A = OH, B = H carbonyl H, H H, H Me Me                               2214 1 0 A = OH, B = H carbonyl H, H H, H Me Me                               2215 2 0 A = OH, B = H carbonyl H, H H, H Me Me                               2216 0 0 A = OH, B = H carbonyl H, H Me, Me H H                               2217 1 0 A = OH, B = H carbonyl H, H Me, Me H H                               2218 2 0 A = OH, B = H carbonyl H, H Me, Me H H                               2219 0 0 A = OH, B = H carbonyl H, H H, H H OMe                               2220 1 0 A = OH, B = H carbonyl H, H H, H H OMe                               2221 2 0 A = OH, B = H carbonyl H, H H, H H OMe                               2222 0 0 A = OH, B = H carbonyl H, H H, H H OEt                               2223 1 0 A = OH, B = H carbonyl H, H H, H H OEt                               2224 2 0 A = OH, B = H carbonyl H, H H, H H OEt                               2225 0 1 A = OH, B = H carbonyl H, H H, H H H                                 2226 1 1 A = OH, B = H carbonyl H, H H, H H H                                 2227 2 1 A = OH, B = H carbonyl H, H H, H H H                                 2228 0 1 A = OH, B = H carbonyl H, H H, H H Me                                2229 1 1 A = OH, B = H carbonyl H, H H, H H Me                                2230 2 1 A = OH, B = H carbonyl H, H H, H H Me                                2231 0 1 A = OH, B = H carbonyl H, H Me, Me H H                               2232 1 1 A = OH, B = H carbonyl H, H Me, Me H H                               2233 2 1 A = OH, B = H carbonyl H, H Me, Me H H                               2234 0 1 A = OH, B = H carbonyl H, H Me, Me Me H                              2235 1 1 A = OH, B = H carbonyl H, H Me, Me Me H                              2236 2 1 A = OH, B = H carbonyl H, H Me, Me Me H                              2237 0 1 A = OH, B = H carbonyl H, H H, H H OEt                               2238 1 1 A = OH, B = H carbonyl H, H H, H H OEt                               2239 2 1 A = OH, B = H carbonyl H, H H, H H OEt                               2240 0 2 A = OH, B = H carbonyl H, H H, H H H                                 2241 1 2 A = OH, B = H carbonyl H, H H, H H H                                 2242 2 2 A = OH, B = H carbonyl H, H H, H H H                               __________________________________________________________________________

                                      TABLE 2-3                                   __________________________________________________________________________    Structure of Compound: formula [1], Z = [1b]                                  Comp. No.                                                                           n m A, B  X, Y                                                                              R1, R2                                                                            R7, R8                                                                             R9  R10                                          __________________________________________________________________________    2301  0 0 double bond                                                                         H, OH                                                                             H, H                                                                              H, H H   H                                              2302 1 0 double bond H, OH H, H H, H H H                                      2303 2 0 double bond H, OH H, H H, H H H                                      2304 0 0 double bond H, OH H, H H, H H H                                      2305 1 0 double bond H, OH H, H H, H H H                                      2306 2 0 double bond H, OH H, H H, H H H                                      2307 0 0 double bond H, OH H, H H, H Pentyl H                                 2308 1 0 double bond H, OH H, H H, H Pentyl H                                 2309 2 0 double bond H, OH H, H H, H Pentyl H                                 2310 0 0 double bond H, OH H, H H, H Me H                                     2311 1 0 double bond H, OH H, H H, H Me H                                     2312 2 0 double bond H, OH H, H H, H Me H                                     2313 0 0 double bond H, OH H, H H, H Me Me                                    2314 1 0 double bond H, OH H, H H, H Me Me                                    2315 2 0 double bond H, OH H, H H, H Me Me                                    2316 0 0 double bond H, OH H, H Me, Me H H                                    2317 1 0 double bond H, OH H, H Me, Me H H                                    2318 2 0 double bond H, OH H, H Me, Me H H                                    2319 0 0 double bond H, OH H, H H, H H OMe                                    2320 1 0 double bond H, OH H, H H, H H OMe                                    2321 2 0 double bond H, OH H, H H, H H OMe                                    2322 0 0 double bond H, OH H, H H, H H OEt                                    2323 1 0 double bond H, OH H, H H, H H OEt                                    2324 2 0 double bond H, OH H, H H, H H OEt                                    2325 0 1 double bond H, OH H, H H, H H H                                      2326 1 1 double bond H, OH H, H H, H H H                                      2327 2 1 double bond H, OH H, H H, H H H                                      2328 0 1 double bond H, OH H, H H, H H Me                                     2329 1 1 double bond H, OH H, H H, H H Me                                     2330 2 1 double bond H, OH H, H H, H H Me                                     2331 0 1 double bond H, OH H, H Me, Me H H                                    2332 1 1 double bond H, OH H, H Me, Me H H                                    2333 2 1 doubie bond H, OH H, H Me, Me H H                                    2334 0 1 double bond H, OH H, H Me, Me Me H                                   2335 1 1 double bond H, OH H, H Me, Me Me H                                   2336 2 1 double bond H, OH H, H Me, Me Me H                                   2337 0 1 double bond H, OH H, H H, H H OEt                                    2338 1 1 double bond H, OH H, H H, H H OEt                                    2339 2 1 double bond H, OH H, H H, H H OEt                                    2340 0 2 double bond H, OH H, H H, H H H                                      2341 1 2 double bond H, OH H, H H, H H H                                      2342 2 2 double bond H, OH H, H H, H H H                                    __________________________________________________________________________

The production of a vitamin D₃ derivative expressed by the above formula[1] can be carried out, for example, by reacting an aldehyde expressedby the following formula [2] with a compound expressed by the followingformula [3] or the following formula [4] in aldol reaction in thepresence of a basic catalyst and optionally combining reactions ofdehydration, deprotection, reduction, isomerization, etc. ##STR3##[wherein, R₁, R₂, R₁₀, n and m are same as defined in the above formula[1]; R_(3a) and R_(4a) are identical to or different from each other,and they are each a hydrogen atom, a hydroxyl group, a protectedhydroxyl group, a C₂ -C₈ acyloxy group, a C₁ -C₇ alkyloxy group, a C₁-C₆ alkylthio group or a C₁ -C₇ alkyl group which is optionallysubstituted with a hydroxyl group, a protected hydroxyl group, a C₂ -C₈acyloxy group or a C₁ -C₇ alkyloxy group; R_(5a), R_(6a), R_(7a) andR_(8a) are same to or different from each other, and they are each ahydrogen atom, a hydroxyl group, a protected hydroxyl group, a C₁ -C₇alkyl group or a C₂ -C₈ acyloxy group; R_(9a) is a hydrogen atom, ahydroxyl group, a protected hydroxyl group, a C₁ -C₇ alkyl group or a C₁-C₆ alkylthio group].

A vitamin D₃ derivative expressed by [1] (Z is [1a]; A is a hydroxylgroup and B is a hydrogen atom; X and Y together express a carbonylgroup in cooperation with the carbon atom to which they are bonded) or[1] (Z is [1b]; A is a hydroxyl group and B is a hydrogen atom; X and Ytogether express a carbonyl group in cooperation with the carbon atom towhich they are bonded), or a vitamin D₃ derivative expressed by [1] (Zis [1a]; A and B together express a double bond (E-configuration) as awhole; X and Y together express a carbonyl group in cooperation with thecarbon atom to which they are bonded) or [1] (Z is [1b]; A and Btogether express a double bond (E-configuration) as a whole; X and Ytogether express a carbonyl group in cooperation with the carbon atom towhich they are bonded) is obtained through aldol reaction between analdehyde expressed by the above formula [2] and a compound expressed bythe above formula [3] or formula [4], and then optionally throughdeprotection in the case where R_(3a) to R_(9a) are each a protectedhydroxyl group.

The vitamin D₃ derivatives expressed by [1] (Z is [1a]; A is a hydroxylgroup and B is a hydrogen atom; X and Y together express a carbonylgroup in cooperation with the carbon atom to which they are bonded) or[1] (Z is [1b]; A is a hydroxyl group and B is a hydrogen atom; X and Ytogether express a carbonyl group in cooperation with the carbon atom towhich they are bonded) can be converted into the vitamin D₃ derivativesexpressed by [1] (Z is [1a]; A and B together express a double bond(E-configuration) as a whole; X and Y together express a carbonyl groupin cooperation with the carbon atom to which they are bonded) or [1] (Zis [1b]; A and B together express a double bond (E-configuration) as awhole; X and Y together express a carbonyl group in cooperation with thecarbon atom to which they are bonded) by subjecting them to dehydrationreactions.

Examples of the basic catalyst in the above aldol reaction include, forexample, an inorganic basic catalyst such as potassium carbonate,lithium hydroxide, sodium hydroxide, potassium hydroxide, calciumhydroxide or sodium hydride, an organic basic catalyst such as1,8-diazabicyclo[5.4.0]undecene (DBU), and an organo metallic basiccatalyst such as lithium diisopropylamide, lithiumhexamethyldisilylamide or sodium hexamethyldisilylamide. Especially,sodium hydroxide, potassium hydroxide, lithium diisopropylamide orlithium lo hexamethyldisilylamide is cited as a preferable example. Theamount of the basic catalyst to be used is 0.1-10 equivalent, preferably0.5-3 equivalent based on the aldehyde to be used as a raw material.Further, an additive for stimulating the reaction is optionally added tothe reaction system. Here, an aldehyde expressed by the above formula[2] carries out stoichiometrically equimolar reaction with a compoundexpressed by the above formula [3] or [4], but it is preferable thateither of which is easier in availability is used in a little excessthan the other for certainly completing the reaction.

Examples of the organic solvent to be used in the aldol reaction includean alcoholic solvent such as methanol or ethanol, a halogen containingsolvent such as methylene chloride, chloroform or carbon tetrachloride,a hydrocarbon solvent such as hexane or toluene, an ether solvent suchas tetrahydrofuran or dioxane, a water-soluble solvent such asN,N-dimethylformamide or acetonitrile, their mixture, etc. The solventcan be selected considering the solubility and the reactivity of acompound. As for reaction temperature, a temperature in the range from-78° C. to the boiling point of the solvent is generally used. Reactiontime generally depends on the basic catalyst, the reaction solvent andthe reaction temperature used. It is commonly preferable that thereaction is continued until either of the compound expressed by theabove formula [3] or [4], or the aldehyde expressed by the above formula[2] disappears when determined by using an analytical means such as thinlayer chromatography.

Examples of the dehydrating agent to be used in the dehydration reactioninclude an acid such as potassium hydrogensulfate, oxalic acid,p-toluenesulfonic acid, iodine or anhydrous copper sulfate, ahalogenating agent such as thionyl chloride or phosphoric acid chloride,a sulfonating agent such as methanesulfonyl chloride, etc. The amount ofthe agent to be used is 1-10 equivalent, preferably 1-5 equivalent basedon an aldol adduct [1] (Z is [1a]; A is a hydroxyl group and B is ahydrogen atom; X and Y together express a carbonyl group in cooperationwith the carbon atom to which they are bonded) or [1] (Z is [1b]; A is ahydroxyl group and B is a hydrogen atom; X and Y together express acarbonyl group in cooperation with the carbon atom to which they arebonded).

By reducing the carbonyl group on the side chain of a vitamin D₃derivative thus obtained expressed by [1] (Z is [1a]; A and B togetherexpress a double bond (E-configuration) as a whole; X and Y togetherexpress a carbonyl group in cooperation with the carbon atom to whichthey are bonded) or [1] (Z is [1b]; A and B together express a doublebond (E-configuration) as a whole; X and Y together express a carbonylgroup in cooperation with the carbon atom to which they are bonded), avitamin D₃ derivative expressed by the following formula [1] (Z is [1a];A and B together express a double bond (E-configuration) as a whole; oneof X and Y is a hydrogen atom, and the other is a hydroxyl group) or [1](Z is [1b]; A and B together express a double bond (E-configuration) asa whole; one of X and Y is a hydrogen atom, and the other is a hydroxylgroup) can be obtained. ##STR4##

In this reductive reaction, sodium borohydride-cesium chloride,diilsobutylaluminum hydride (DIBAH), 9-borabicyclo[3.3.1]nonane (9-BBN),lithium n-butylborohydride, K-Selectride®, tri-i-butylaluminium, etc.,may be used as a reducing agent.

Similar reductive reaction may be carried out on a vitamin D₃ derivativeexpressed by [1] (Z is [1a]; A is a hydroxyl group and B is a hydrogenatom; X and Y together express a carbonyl group in cooperation with thecarbon atom to which they are bonded) or [1] (Z is [1b]; A is a hydroxylgroup and B is a hydrogen atom; X and Y together express a carbonylgroup in cooperation with the carbon atom to which they are bonded), andin this case, a vitamin D₃ derivative expressed by the following formula[1] (Z is [1a]; A is a hydroxyl group and B is a hydrogen atom; one of Xand Y is a hydrogen atom, and the other is a hydroxyl group) or [1] (Zis [1b]; A is a hydroxyl group and B is a hydrogen atom; one of X and Yis a hydrogen atom, and the other is a hydroxyl group) can be obtained.##STR5##

Further, [1] (Z is [1a]; A and B together express a double bond(E-configuration) as a whole; one of X and Y is a hydrogen atom, and theother is a hydroxyl group), which is obtained by the above reductivereaction, can be converted into a vitamin D₃ derivative expressed by [1](Z is [1a]; A is a hydrogen atom and B is a hydroxyl group; X and Ytogether express a carbonyl group in cooperation with the carbon atom towhich they are bonded) by epoxidizing of the double bond at the α,β-position of the ketone on the side chain and subsequently treating theresultant epoxy ring for reductive ring opening reaction, and thencarrying out oxidation of secondary hydroxy group. ##STR6##

Furthermore, as shown below, the reduction of the double bond at the α,β-position of the ketone on the side chain of the above formula [1] (Zis [1]; A and B together express a double bond (E-configuration) as awhole; X and Y together express a carbonyl group in cooperation with thecarbon atom to which they are bonded) can obtain a vitamin D₃ derivativeexpressed by the following formula [1] (Z is [1]; both of A and B areeach a hydrogen atom; X and Y together express a carbonyl group incooperation with the carbon atom to which they are bonded). ##STR7##

In this reductive reaction, reduction with sodium borohydride, Na₂ S₂O₄, NaHTe, tri-n-butyltin hydride, K-Selectride® or lithium aluminumhydride-cuprous iodide(l), or Birch reduction, etc., is applicable.

Further, as shown below, the isomerization of the double bond at the α,β-position of the ketone on the side chain of the above formula [1] (Zis [1]; A and B together express a double bond (E-configuration) as awhole; X and Y together express a carbonyl group in cooperation with thecarbon atom to which they are bonded) can obtain a vitamin D₃ derivativeexpressed by the following formula [1] (Z is [1c]; X and Y togetherexpress a carbonyl group in cooperation with the carbon atom to whichthey are bonded) or a vitamin D₃ derivative expressed by the followingformula [1] (Z is [1]; A and B together express a double bond(Z-configuration) as a whole; X and Y together express a carbonyl groupin cooperation with the carbon atom to which they are bonded). ##STR8##

In this isomerization, a transition metal compound such as rhodiumchloride or ultraviolet rays may be used.

Thus obtained compounds expressed by the above formula [1] optionallycan be converted into vitamin D₃ derivatives expressed by the followingformula [1] in which R₁ and R₂ are each hydrogen by subjecting todeprotection reaction.

The conversions of side chains of vitamin D₃ derivatives of the presentinvention will be precisely explained in examples.

The deprotection reaction may be carried out according to a known method(for example, Caverly, Tetrahedron, 20, 4609-4619 (1987)), and as thedeprotecting agent, for example, tetrabutyl-ammonium fluoride,pyridinium p-toluenesulfonate, hydrogen fluoride, etc., may be used.Examples of the organic solvent to be used in the reaction include ahalogen-containing solvent such as methylene chloride, chloroform orcarbon tetrachloride, a hydrocarbon solvent such as hexane or toluene,an ether solvent such as tetrahydrofuran or dioxane, a water-solublesolvent such as N,N-dimethylformamide or acetonitrile, a mixed solventof them, etc. The solvent may be selected in consideration of thesolubility and the reactivity of the compound. The reaction temperatureis commonly ranging from -20° C. to the boiling point of the solvent.The reaction time depends on the dehydrating agent, deprotecting agent,reaction solvent and reaction temperature used, and it is commonlypreferable that the reaction is continued until the starting materialdisappears when determined by using an analytical means such as thinlayer chromatography.

Further, in the deprotection reaction, the deprotection of a vitamin D₃derivative expressed by the above formula [1] in which R₁ and R₂ aretri(C₁ -C₇ alkyl)silyl groups may be carried out by using a reagentconsisting of a combination of an alkali metal salt of tetrafluoroboricacid and a mineral acid. As the alkali metal salt of tetrafluoroboricacid, lithium tetrafluoroborate, sodium tetrafluoroborate or potassiumtetrafluoroborate may be used, and as the mineral acid, hydrochloricacid, sulfuric acid, etc., may be used. It is preferable that an alkalimetal salt of tetrafluoroboric acid is used in an amount of 1-3equivalent based on the hydroxyl group to be deprotected, and a mineralacid is used in an amount of 0.05-3 equivalent. To the reaction solvent,reaction temperature and reaction time, similar conditions to in thecase of the above deprotection reaction may be applied. Especially, whenacetonitrile or methylene chloride is ued as the solvent, the reactiontemperature is preferably from 0° C. to room temperature, and thereaction time is preferably from 10 min to about 1 hr.

Furthermore, the deprotection reaction using the reagent consisting of acombination of an alkali metal salt of tetrafluoroboric acid and amineral acid is applicable generally to vitamin D₃ derivatives whosehydroxyl groups at 1- and 3-positions are protected with tri(C₁ -C₇alkyl)silyl groups.

Aldehydes expressed by the above formula [2] may be synthesized, forexample, according to the following schemes.

An aldehyde whose n is 0 can be obtained from vitamin D₂ by a knownmethod (the International Patent Publication WO90/0991; Caverly,Tetrahedron, 20, 4609-4619 (1987)). An aldehyde compound whose n is 1 or2 can be obtained by the combination of known processes as shown infollowing Scheme 1 or Scheme 2. ##STR9##

In addition, compounds expressed by the above formulae [3] and [4] arecommercial products or are producible by combining known methods.##STR10##

Further, a vitamin D₃ derivative expressed by the above formula [1] ofthe present invention may be produced also by the following productionmethod. That is, a vitamin D₃ derivative expressed by the above formula[1] can be obtained by subjecting a compound expressed by the followingformula [5] and an ene-yne compound expressed by the following formula[6] to coupling in the presence of a palladium catalyst.

Furthermore, the obtained derivative optionally can be converted into avitamin D₃ derivative expressed by the above formula [1] whose R₁ and R2are each a hydrogen atom by currying out deprotection reaction.##STR11## [herein, R₁ to R₁₀, A, B, X, Y, n, and m are same as thosedefined in the above formula [1]; Q is a bromine atom or an iodineatom].

As the palladium catalyst in the coupling reaction, for example, amixture of a 0- or 2-valent organic palladium compound and atrisubstituted phosphorus compound [molar ratio is (1:1) to (1:10)] isused. Examples of the palladium compound may include, for example,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)palladium(0)-chloroform adduct and palladiumacetate. Further, examples of the trisubstituted phosphorus compoundinclude triphenylphosphine and tributylphosphine. As a preferableexample of the palladium catalyst, a combination oftris-(dibenzylidene-acetone)dipalladium(0)-chloroform adduct andtriphenylphosphine [(1:1) to (1:10)] may be cited. Furthermore, apalladium catalyst is used in an amount in the range of 1-100 mol %,preferably 5-30 mol % based on a compound expressed by the above formula[5]. Herein, a compound expressed by the above formula [5] and anene-yne compound expressed by the above formula [6] performstoichiometrically equimolar reaction, but it is preferable that eitherof which is easier in availability is used in a little excess than theother for certainly completing the reaction.

Examples of the organic solvent to be used in the coupling reactioninclude a hydrocarbon solvent such as hexane or toluene, an ethersolvent such as tetrahydrofuran or dioxane, a water-soluble solvent suchas N,N-dimethylformamide or acetonitrile, a mixed solvent of them, etc.,and they are preferably used after sufficient deaeration. As thereaction temperature, a temperature ranging from room temperature to theboiling temperature of the solvent is commonly used. The reaction timedepends on the reaction solvent and the reaction temperature used in thereaction, and it is commonly preferable that the reaction is continueduntil either of a cycloalkanone compound expressed by the above formula[5] and an ene-yne compound expressed by the above formula [6]disappears, when determined by using an analytical means such as thinlayer chromatography. Further, it is preferable that the reaction iscarried out, for example, in the presence of a base such astriethylamine or diisopropylamine for trapping hydrogen chloride,besides a palladium catalyst. As for the amount of the base, oneequivalent or more based on a cycloalkanone compound expressed by theabove formula [5] is preferable, and optionally, the base may be used asa solvent at the same time. Further, the deprotection reaction may beperformed according to the above-mentioned method.

A compound expressed by the above formula [5] to be used as a rawmaterial in the production method of the present invention may beproduced, for example, by reacting a compound expressed by the followingformula [7] with a compound expressed by the following formula [3] or[4] in aldol reaction and optionally treating the reaction product fordehydration, deprotection, reduction, isomerization, etc., as shown inScheme 3. These reactions are carried out substantially in the samemanner as the above-mentioned aldol reaction that is carried out betweena compound expressed by the above formula [2] and a compound expressedby the above formula [3] or [4], and dehydration, deprotection,reduction, isomerization, etc., which are optionally carried outfollowing the aldol reaction, to produce a compound expressed by theabove formula [1]. ##STR12##

Further, compound [7] used in the above Scheme 3 may be produced bycombining known methods as shown in Scheme 4 (n=0), Scheme 5 (n=1) andScheme 6 (n=2). ##STR13##

Further, compounds expressed by the above formulae [3] and [4] arecommercial products or producible by combining known methods.

Thus obtained vitamin D₃ derivatives is optionally converted into apharmaceutically permissible solvate as shown above.

Furthermore, the present invention provides treating agents forinflammatory respiratory diseases containing above vitamin D₃derivatives in therapeutically effective amounts and also methods fortreating the diseases using the agents.

The inflammatory respiratory diseases to be objective of the treatingagents or the treating methods of the present invention includes, forexample, one or not less than two kinds of inflammatory respiratorydiseases selected from a group consisting of acute upper airwayinfection, chronic sinusitis, allergic rhinitis, chronic lowerrespiratory infection, pulmonary emphysema, pneumonia, asthma, pulmonarytuberculosis sequela, acute respiratory distress syndrome and pulmonaryfibrosis.

Especially, one or not less than two kinds of acute upper airwayinfections selected from a group consisting of, for example, commoncold, acute pharyngitis, acute rhinitis, acute sinusitis, acutetonsillitis, acute laryngitis, acute epiglottitis and acute bronchitis,or one or not less than two kinds of chronic lower airway infectionsselected from a group consisting of, for example, chronic bronchitis,diffuse panbronchiolitis and bronchiectasis are preferably cited asinflammatory respiratory disease which is objective of the presentinvention.

Further, the present invention provides treating agents for malignanttumors containing above vitamin D₃ derivatives as active ingredients intherapeutically effective amounts and also provides therapeutic methodsfor the diseases using the agents. The treating agents may beadministered for reducing the sizes or suppressing the growths of tumorcites after confirmed diagnosis of cancer, or for preventing therecurrence of the cancer after surgical operation or radiotherapy.Further, the kind of malignant tumor to be objective is not specificallyrestrictive, but especially, leukemia, colon cancer, prostaticcarcinoma, breast cancer, lung cancer, brain tumor and melanoma may becited as preferable objectives.

Furthermore, the present invention provides treating agents for diseasesselected from a group consisting of rheumatoid arthritis, osteoporosis,diabetes mellitus, hypertension, alopecia, acne, psoriasis anddermatitis which contain vitamin D₃ derivatives or pharmaceuticallypermissible solvates thereof in therapeutically effective amounts andmethods for treating a group of the diseases using the treatingreagents.

Treating agents for various diseases of the present invention can beadministered orally, or parenterally through intravenous, subcutaneous,intramuscular, percutaneous, intranasal or intrarectal route, or byinhalation.

Dosage forms for oral administration include tablets, pills, powders,granules, liquids, suspensions, syrups, capsules, etc.

The tablets are formulated according to a conventional process by usingadditives consisting of an excipient such as lactose, starch, calciumcarbonate, crystalline cellulose or silicic acid; a binder such ascarboxymethylcellulose, methylcellulose, calcium phosphate orpolyvinylpyrrolidone; a disintegrator such as sodium alginate, sodiumbicarbonate, sodium laurylsulfate or stearic acid monoglyceride; ahumectant such as glycerin; an absorbent such as kaolin or colloidalsilica; a lubricant such as talc or granular boric acid, etc.

The pills, powders and granules are prepared by conventional processesalso using additives similar to those mentioned above.

Liquid preparations such as the liquids, suspensions and syrups can beformulated also according to conventional processes. As a carrier, forexample, a glycerol ester such as tricaprylin, triacetin or an iodizedpoppy oil fatty acid ester; water; an alcohol such as ethanol; and anoily base such as liquid paraffin, coconut oil, soybean oil, sesame oilor corn oil is used.

The capsules are formulated by filling a powdery, granular or liquidpharmaceutical composition, etc., in gelatin capsules, etc.

Dosage forms for intravenous, subcutaneous and intramuscularadministration include injections in the forms of sterilized aqueoussolutions, non-aqueous solutions, etc. In an aqueous solution, forexample, a physiological saline solution, etc., is used as a solvent. Ina non-aqueous solution, for example, propylene glycol, polyethyleneglycol, a vegetable oil such as olive oil, an organic ester which isacceptable for injection such as ethyl oleate or an iodized poppy oilfatty acid ester, etc., is used as a solvent. To the pharmaceuticalpreparations for injection are optionally added an isotonizing agent, apreservative, a humectant agent, an emulsifier, a dispersant, astabilizer, etc., and the preparation may be sterilized by an adequatetreatment such as filtration through a bacterium-retaining filter,blending of a germicide or irradiation. Also, the preparation may beprepared as aseptic solid preparation, which is used by dissolving insterilized water or a sterilized solvent for injection just prior touse.

Further, a compound of the present invention may be used in the form ofa clathrate compound prepared using α, β or γ-cyclodextrin, a methylatedcyclodextrin, etc. The compound may be used also as an injection oflipoid form.

Dosage forms for percutaneous administration include ointments, creams,lotions, solutions, etc.

The base of an ointment include, for example, a fatty acid such ascastor oil, olive oil, sesame oil or safflower oil; lanolin; white,yellow or hydrophilic vaseline; wax; a higher alcohol such as oleylalcohol, isostearyl alcohol, octyldodecanol or hexyldecanol; a glycolsuch as glycerin, diglycerin, ethylene glycol, propylene glycol,sorbitol or 1,3-butanediol; etc. Further, as a solubilizing agent for acompound of the present invention, ethanol, dimethyl sulfoxide,polyethylene glycol, etc., may be compounded. Optionally, a preservativesuch as a paraoxybenzoic acid ester, sodium benzoic acid, salicylicacid, sorbic acid or boric acid; an antioxidant such asbutylhydroxyanisole or dibutylhydroxytoluene; etc., may be added.

Further, for stimulating percutaneous absorption in an ointment, anabsorption promoter such as diisopropyl adipate, diethyl sebacate, ethylcaproate or ethyl laurate may be compounded. Also, for stabilization, acompound of the present invention may be used in the form of a clathratecompound prepared using α, β or γ-cyclodextrin, a methylatedcyclodextrin, etc. An ointment can be prepared by a conventionalprocess.

For the creams, dosage forms of oil-in-water type are preferable forstabilizing compounds of the present invention. Further, theabove-mentioned fatty oil, higher alcohol, glycol, etc., can be used asthe base of a cream, and diethylene glycol, propylene glycol, sorbitanmono fatty acid ester, polysorbate 80, sodium laurylsulfate, etc., isused as the emulsifier of a cream. Further, the above-mentionedpreservative, antioxidant, etc., may be added. Furthermore, as in thecase of ointment, a compound of the present invention can be used in theform of a clathrate compound prepared using a cyclodextrin or amethylcyclodextrin. A cream can be prepared according to a conventionalprocess.

Examples of the lotions include a suspension-type lotion, anemulsion-type lotion and a solution-type lotion. The suspension-typelotion is prepared by using a suspending agent such as sodium alginate,traganth or sodium carboxymethylcellulose, and optionally by adding anantioxidant, a preservative, etc.

The emulsion-type lotion is prepared according to a conventional processusing an emulsifier such as sorbitan mono fatty acid ester, polysorbate80 or sodium laurylsulfate. A compound of the present invention isdissolved in an alcohol such as ethanol, and optionally an antioxidant,a preservative, etc., are added.

Besides the above-mentioned dosage forms, a pasta, a poultice, anaerosol, etc., may be cited. The pharmaceutical preparations havingthese dosage forms can be prepared according to conventional processes.

Pharmaceutical preparations for intranasal administration are suppliedin the form of a liquid or powdery composition. As the base of theliquid preparation, water, saline, a phosphate buffer solution, anacetate buffer solution, etc., is used, and the liquid preparation maycontain further a surfactant, an antioxidant, a stabilizer, apreservative and/or a thickener. As the base for the powderypreparation, a water-absorbent base is preferable. The examples of thewater-absorbent base include polyacrylate salts such as sodiumpolyacrylate, potassium polyacrylate and ammonium polyacrylate;cellulose lower-alkyl ethers such as methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose and sodiumcarboxymethylcellulose; polyethylene glycol; polyvinyl pyrrolidone;amylose; pullulan, etc., which are soluble in water, and cellulosecompounds such as crystalline cellulose, α-cellulose and cross-linkedsodium carboxymethylcellulose; starch compounds such as hydroxypropylstarch, carboxymethyl starch, cross-linked starches, amylose,amylopectin and pectin; proteins such as gelatin, casein and sodiumcaseinate; gums such as gum arabic, tragacanth gum and glucomannan gum;polyvinylpolypyrrolidone, cross-linked polyacrylic acid and saltsthereof, cross-linked polyvinyl alcohols, etc., which are scarcelysoluble in water. These compounds may be used alone or in mixtures oftwo or more thereof. The powdery preparation may be further compoundedwith an antioxidant, a coloring agent, a preservative, a disinfectant,an antiseptic, etc. These liquid and powdery preparations can beapplied, for example, each by using a spraying device, etc.

For intrarectal administration, ordinary suppositories such as gelatinsoft capsule are used.

Further, for inhalation, a powdery or liquid composition prepared usingan active ingredient of a vitamin D₃ derivative of the present inventionalone or in combination with an adequate biocompatible vehicle can beadministered to disease sites by using an applicator such as a sprayingdevice, a nebulizer or an atomizer. Alternatively, an active ingredientmay be administered to disease sites in a dosage form prepared bysuspending in a spraying agent for aerosol such as flon.

A pharmaceutically effective dose of an active ingredient of the presentinvention depends on administration route, age and sex of the patient,objective disease, and the conditions of the disease, but it isordinarily about 0.001-100 μg per day, preferably about 0.1-10 μg perday, and administration frequency is ordinarily 1-3 time per day. Thepharmaceutical preparation is preferably prepared so as to meet theseconditions.

Further, treating agents of the present invention for various kinds ofdiseases can be administered in combination with conventional medicines.

Effectiveness for inflammatory respiratory diseases of vitamin D₃derivatives expressed by the above formula [1] of the present inventionhas been demonstrated by experiments using LPS-induced airwayinflammatory hamsters, which are widely used as an inflammatorypulmonary disease model, as shown concretely in the following examples.That is, it has been found that compounds of the present inventionsignificantly suppress LPS-induced airway inflammatory byintra-respiratory tract administration or oral administration.

Further, effectiveness for malignant tumors of vitamin D₃ derivativesexpressed by the above formula [1] of the present invention has beendemonstrated by experiments using human leukemia cells (HL-60), humancolon cancer cells (HT-29) or cancer cell-transplanted mice as shownconcretely in the following examples. That is, it has been found thatvitamin D₃ derivatives of the present invention exhibit thedifferentiation inducing effect on human leukemia cells (HL-60) and thegrowth suppressing effect on human colon cancer cells (HT-29), and theysuppress the growth of the cancer cells of cancer cell-transplanted miceby oral administration.

On the other hand, it has been clarified that the blood calciumlevel-elevation effects of compounds of the present invention isextremely reduced compared with that of 1 α,25-dihydroxyvitamin D₃although the generally most worried side effect of active vitamin D₃compounds is the elevation of calcium level in blood. For example, theblood calcium level-elevation effects of vitamin D₃ derivatives of thepresent invention in oral administration to rats, which are comparedwith that of 1 α,25-dihydroxyvitamin D₃, are as shown below:

Compound No. 1101, 1/>500,

Compound No. 1105b, 1/17

Compound No. 1110b, 1/111

Compound No. 1112b, 1/27

Compound No. 1126b, 1/47

Compound No. 1126d, 1/115

Compound No. 1127a, 1/41

Compound No. 1127b, 1/79

Compound No. 1128a, 1/16

Compound No. 1128b, 1/11

Compound No. 1129b, 1/55

Compound No. 1130b, 1/11

Compound No. 1131a, 1/10

Compound No. 1401a, 1/158.

From the above results, it is confirmed that in vitamin D₃ derivativesexpressed by the above formula [1], the separation of the developmentconcentrations for anti-inflammatory effect and anti-malignant tumoreffect from that for blood calcium level elevation effect has beenachieved, and side effect will not be generated.

Thus, treating agents containing vitamin D₃ derivatives expressed by theabove formula [1] as active ingredients can be considered to beeffective for inflammatory respiratory diseases or malignant tumors.

By the way, it has been reported that an active vitamin D₃ has variouseffects on cell metabolism. Examples of such reports include thestimulation of maturation and differentiation of cell (Tanaka, et al.,Biochem. J., 204, 713-719 (1982); Amento, et al., J. Clin. Invest., 73,731-739 (1984); Colston, et al., Endocrinology, 108, 1083-1086 (1981);Abeetl, et al., Proc. Natl. Acad. Sci., 78, 4990-4994 (1981)) andimmunosuppression effect such as interleukin-2 production inhibition(Rigby, Immunology Today, 9, 54-58 (1988)). In addition, also immunologysynergistic effect has been detected, and the stimulation of heproduction of bactericidal oxygen metabolites and the stimulation ofleukocyte chemotactic response has been discovered.

It has been recognized that also vitamin D₃ derivatives expressed by theabove formula [1] have the cell differentiation-inducing effect asmentioned above. This fact demonstrates that vitamin D₃ derivativesexpressed by the above formula [1] have possibilities of therapies invarious fields including, for example, psoriasis, rheumatoid arthritis,inflammatory diseases such as dermatitis and autoimmune diseases, andsupplementary agents in chemotherapy of infectious diseases (especially,bacterial, viral or fungus) and other therapies associated withmononuclear phagocyte.

Further, it has been reported that an active vitamin D₃ is effective inthe treatment of hypertension (Lind, et al., Acta Med. Scand., 222,423-427 (1987)), the treatment of diabetes mellitus (Inomata, et al.,Bone Mineral, 1, 187-192 (1986)), the stimulation of hair growth(Lancet, March 4, 478 (1989)) and the treatment of acne (Malloy, et al.,Tricontinental Meeting for Investigative Dermatology, Washington, 1989),and it is expected that vitamin D₃ derivatives of the present inventionare also effective on these treatments.

Some of vitamin D₃ derivatives expressed by the above formula [1] arevery high binding affinties bonding to 1 α,25-dihydroxyvitamin D₃receptor, that is, they have binding affinties ranging from same degreeto 1/50 of 1 α,25-dihydroxyvitamin D₃, and high vitamin D₃ -like effectscan be expected in them.

Also, in assay systems using other cell lines, for example, a compoundNo. 1127a accelerated collagen synthesis and non-collagen proteinsynthesis in mouse osteoblastic cell line (MCJT) in a dose-relatedmanner. The collagen synthesis acceleration effect of the compound No.1127a was stronger than that of 1 α,25-dihydroxyvitamin D₃. Further, inthe compound, calcification acceleration effect has also been detectedin human osteoblastic cell line (SAM-1). Further, when the formationacceleration effect of osteoclast was assayed, compounds No. 1128a and1130a exhibited significant osteoclast formation acceleration effects.This suggests that these compounds activate bone metabolism turnoveraccompanied by the osteoclast formation acceleration, and thus they havepossibility to become treating agents for osteoporosis.

EXAMPLES

The present invention will be explained further in detail hereafter withexamples, while the present invention is not restricted by the examples.The compound number in each example corresponds to the compound numbershown in the above Table 1--1 to Table 1-14 or Table 2-1 to Table 2-3. Acompound number having an alphabet shows a stereoisomer (includinggeometrical isomer) of the compound.

Reference Example 1

Production of compound 7 (n=0) ##STR14##

In 50 ml of methylene chloride was dissolved [a] (2.15 g) at roomtemperature, and the resultant solution was cooled with ice. To thecooled solution were serially added diisopropylethylamine (1.58 g) andt-butyldimethylsilyl chloride (1.54 g), and the mixture was stirredovernight after it was warmed up to room temperature. The reactionmixture was poured into ice-cooled water and extracted with methylenechloride. The organic layer was washed with brine, dried over sodiumsulfate anhydride and evaporated to obtain crude [b].

The obtained [b] was dissolved in 20 ml of methylene chloride and cooledwith ice. A mixture of pyridinium chlorochromate (PCC) (3.3 g) andcelite (about 3 g) was added to the solution, and the mixture was warmedup to room temperature. After stirring for 2.5 hr, the reaction mixturewas filtered, and the filtrate was concentrated and purified by silicagel column chromatography (hexane:ethyl acetate=20:1) to obtain [c] (3.2g, 98% yield).

¹ H NMR (CDCl₃) δ: 3.33, (dd, J=2.6, 9.6 Hz, 1 H), 2.57 (dd, J=2.6, 9.6Hz, 1 H), 2.27 (dd, J=2.6, 6.3 Hz, 1 H), 1.23-2.29 (m, 1 H), 1.03 (d,J=6.3 Hz, 3 H), 0.89 (s, 9 H), 0.65 (s, 3 H), 0.03 (s, 6 H).

A container having 0.45 g of molecular sieve 4A in it was heated underreduced pressure with a heat gun to be dried.Bromomethyltriphenylphosphine bromide (13.26 g) and 70 ml oftetrahydrofuran were added to this, and the mixture was cooled to -70°C.To this mixture was added dropwise 26 ml of 1 M-tetrahydrofuran solutionof sodium bistrimethylsilylamide while the temperature was slowlyelevated up to -40° C. The mixture was cooled again down to -78° C. andadded dropwise to a solution of [c] (1.23 g) in tetrahydrofuran (15 ml),which had been cooled to -15° C., through a cannula. After thecompletion of the addition, the mixture was continuously stirred as itwas for 30 min. The reaction mixture was poured into hexane havingsuspended silica gel, the resultant mixture was filtered through celite,and the silica gel was washed with ethyl acetate. The filtrate wasevaporated, and the residue was purified with silica gel columnchromatography (hexane:ethyl acetate=100:1 to 10:1) to obtain [d] in aform of a mixture with triphenylphosphine.

The obtained [d] was dissolved in 5 ml of methylene chloride and 5 ml ofacetonitrile, and the solution was cooled to 0° C. Lithiumtetrafluoroborate (739 mg) was added to this, and then a solutionprepared by diluting concentrated sulfuric acid with acetonitrile wasadded dropwise. When [d] had disappeared on thin layer chromatography(TLC), water and a saturated sodium bicarbonate solution were added, andthe mixture was extracted with methylene chloride. The organic layer waswashed with brine, dried and concentrated. The residue was purified withsilica gel column chromatography (hexane: ethyl acetate=5:1 to 4:1) toobtain [e] (660 mg, 59% yield).

¹ H NMR (CDCl₃) δ: 5.66 (d, J=1.7 Hz, 1 H), 3.65 (dd, J=3.3, 10.6 Hz, 1H), 3.40 (dd, J=6.6, 10.6 Hz, 1 H), 2.85-2.90 (m, 1 H), 1.23-2.03 (m, 12H), 1.06 (d, J=6.6 Hz, 3 H), 0.59 (s, 3 H).

The obtained [e] (660 mg) was dissolved in 18 ml of acetone. To thesolution were added N-methylmorpholine-N-oxide (546 mg) andtristriphenylphosphine ruthenium (II) chloride (67 mg), and the mixturewas stirred for 1 hr at room temperature. The reaction mixture waspoured into ether having suspended silica gel, and the mixture wasfiltered through celite. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane: ethyl acetate=30:1 to 1:1) to obtain theobjective product (432 mg, 67% yield).

¹ H NMR (CDCl₃) δ: 9.59 (d, J=3.3 Hz, 1 H), 5.68 (s, 1 H), 2.88-2.93(in, 1 H), 2.32-2.42 (m, 1 H), 2.01-2.10 (in, 2 H), 1.33-1.98 (in, 9 H),1.15 (d, J=6.9 Hz, 3 H) 0.61 (s, 3 H).

Reference Example 2

Production of Compound [7] (n=1) ##STR15##

Bromomethylenetriphenylphosphonium bromide (2.39 g) was placed in a100-ml egg plant-type flask, 40 ml of dry THF was added, and these werestirred and cooled to -70° C. To the solution was added dropwise 5.28 mlof 1M solution of sodium hexamethyldisilazide in THF, and the mixturewas stirred for 1 hr at the same temperature. Subsequently, a solutionprepared by dissolving [f] (300 mg) in 10 ml of dry THF was addeddropwise, and then the mixture was stirred for 1 hr after the coolingbath was removed. Then, the reaction mixture was filtered after hexanewas added to remove insoluble matters, and the filtrate was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane: ethyl acetate=14:1 to 9:1) to obtain [g] (178mg, 48% yield).

¹ H NMR (CDCl₃) δ: 7.78 (d, J=8 Hz, 2 H), 7.35 (d, J=8 Hz, 2 H), 5.64(s, 1 H), 3.96 (dd, J=3, 9 Hz, 1 H), 3.82 (dd, J=6, 9 Hz, 1 H), 2.45(s,3 H), 0.99 (d, J=7 Hz, 3 H), 0.53 (s, 3 H).

In a 50-ml egg plant-type flask, [g] (178 mg) was placed, and 6 ml ofDMF was added to dissolve [g]. KCN (215 mg) was put into the solution,and the mixture was stirred for 24 hr at 50° C. After 50 ml of water wasadded, the reaction mixture was extracted with ether. The organic layerwas washed with water, and then with brine, dried over magnesium sulfateanhydride and evaporated under reduced pressure to obtain a crudeproduct (110 mg). This was purified by silica gel column chromatography(hexane: ethyl acetate'14:1) to obtain [h] (84 mg, 69% yield).

¹ H NMR (CDCl₃) δ: 5.67 (s, 1 H), 2.86-2.91 (m, 1 H), 2.21-2.35 (m, 2H), 1.18 (d, J=6 Hz, 3 H), 0.59 (s, 3 H).

In a 25-ml egg plan-type flask, [h] (84 mg) was placed, and 5 ml of drydichloromethane was added to dissolve [h]. After the mixture was cooledto -70° C., 660 μl of 1.5 M solution of diisobutyl-aluminum hydride intoluene was added dropwise. The mixture was stirred for 1 hr at the sametemperature, then 0.5 ml of a saturated sodium sulfate aqueous solution,0.3 ml of methanol, 0.5 ml of 2N hydrochloric acid and 15 ml of ethylacetate were added, and the resultant mixture was stirred for 30 min.The reaction mixture was filtered through celite, the filtrate waswashed with a saturated ammonium chloride aqueous solution andsubsequently with brine, dried over magnesium sulfate anhydride andevaporated under reduced pressure to obtain the object product (85 mg).

Reference Example 3

Production of Compound [7] (n=2) ##STR16##

In 80 ml of pyridine was dissolved [a] (10.05 g), the solution wascooled to 0° C., 6.1 ml of trimethylacetyl chloride was added, and theresultant mixture was stirred for 1 hr. Subsequently, it was furtherstirred for 1 hr after trimethylsilyl chloride (6.6 ml) was added. Thereaction mixture was poured into ice water, and the mixture wasextracted with ether. The organic layer was washed with a saturatedpotassium hydrogensulfate solution, subsequently washed with water andthen brine, dried over sodium sulfate anhydride and concentrated toobtain crude [i].

An ether solution of the obtained crude [i] was added dropwise to asuspension of potassium t-butoxide (21.2 g) and water (2 ml) in ether(270 ml) at 0° C. The temperature of the mixture was elevated to roomtemperature as it was, and the mixture was stirred overnight. Thereaction mixture was poured into ice water and extracted with ether, andthe organic layer was washed with brine, dried over magnesium sulfateanhydride and concentrated. The residue was purified by silica gelcolumn chromatography (hexane: ethyl acetate=9:1) to obtain [b] (12.86g, 96% yield).

¹ H NMR (CDCl₃) δ: 4.00 (br, 1 H), 3.63 (dd, J=3.3, 10.6 Hz, 1 H), 3.36(dd, J=6.9, 10.6 Hz, 1 H), 1.10-1.96 (m, 13 H), 1.02 (d, J=6.6 Hz, 3 H),0.90 (s, 3 H), 0.05 (s, 9 H).

The obtained [j] was subjected to the same treatment as that forconverting [e] into [7] (n=0) in Reference Example 1, and thus [k] wasobtained.

¹ H NMR (CDCl₃) δ: 9.58 (d, J=3.2 Hz, 1 H), 4.02 (br., 1 H), 2.31-2.41(m, 1 H), 1.24-1.83 (m, 12 H), 1.09 (d, J=6.5 Hz, 3 H), 0.93 (s, 3 H),0.06 (s, 9 H).

To 70 ml of a toluene solution of the obtained [k] (3.46 g) was addedmethyl (triphenylphosphoranylidene)acetate (12.24 g), and the mixturewas heated at reflux overnight. After insoluble matters were filteredoff, the filtrate was evaporated, and the residue was purified by silicagel column chromatography (hexane: ethyl acetate=30:1) to obtain [l](3.88 g, 94% yield).

¹ H NMR (CDCl₃) δ: 6.84 (dd, J=8.9, 15.5 Hz, 1 H), 5.74 (d, J=15.5 Hz, 1H), 3.99 (br., 1 H), 3.72 (s, 3 H), 2.21-2.30 (m, 1 H), 1.11-1.96 (m,12H), 1.06 (d, J=6.3 Hz, 3 H), 0.92 (s, 3 H), 0.05 (s, 9 H).

The obtained [l] (2.08 g) was dissolved in 10 ml of methanol and 5 ml ofethyl acetate. To the resultant solution were added one drop ofconcentrated hydrochloric acid and then, about 100 mg ofpalladium-carbon, and the reaction system was substituted with hydrogen.The mixture was stirred overnight at room temperature as it was, thereaction mixture was filtered, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography (hexane: ethylacetate=4:1) to obtain [m] (1.58 g, 96% yield).

¹ H NMR (CDCl₃) δ: 4.08 (d, J=3.0 Hz, 1 H), 3.66 (s, 3 H), 1.05-2.42 (m,17 H), 0.93 (s, 3 H), 0.90 (d, J=6.6 Hz, 3 H).

Pyridinium dichromate (PDC) (3.64 g) was dissolved in 20 ml ofdimethylformamide, and the solution was cooled to 0° C. To the resultantsolution was added dropwise a solution of the above-obtained [m] (1.29g) in 5 ml of dimethylformamide, and the mixture was stirred for 2 hr asit was. The reaction mixture was poured to a suspension of silica gel ina mixed solvent of hexane: ethyl acetate=2:1, the resultant mixture wasfiltered through celite, and the filtrate was concentrated. The residuewas purified by silica gel column chromatography (hexane: ethylacetate=8:1 to 4:1) to obtain [n] (1.24 g, 97% yield).

¹ H NMR (CDC1₃) δ: 3.67 (s, 3 H), 1.26-2.48 (m, 17 H), 0.96 (d, J=4.6Hz, 3 H), 0.64 (s, 3 H).

The obtained [n] was subjected to the same treatment as that forconverting [c] into [d] in Reference Example 1, and thus [o] wasobtained in 50% yield.

¹ H NMR (CDC1₃) δ: 5.64 (d, J=1.7 Hz, 1 H), 3.66 (s, 3 H), 2.84-2.90 m,1 H), 2.23-2.42 (m, 2 H), 1.21-2.04 (m, 14 H), 0.93 (d, J=6.3 Hz, 3 H),0.56 (s, 3 H).

To a solution of the obtained [o] (292 mg) in 5 ml of methylene chloridewas added at -78° C. 1 ml of 0.93 M hexane solution ofdiisobutylammonium hydride. After the mixture was stirred for 30 min, 2ml of methanol was added and the resultant mixture was well stirred. Tothe reaction mixture was added a saturated ammonium chloride aqueoussolution, the resultant mixture was warmed up to room temperature, andthe reaction mixture was extracted with ethyl acetate. The organic layerwas sequentially washed with a saturated sodium bicarbonate aqueoussolution, water and brine, dried over sodium sulfate anhydride andconcentrated. The residue was purified by silica gel columnchromatography (hexane: ethyl acetate=25:1) to obtain [7] (n=2) (243 mg,91% yield).

¹ H NMR (CDCl₃) δ: 9.78 (t, J=1.8 Hz, 1 H), 5.65 (d, J=1.7 Hz, 1 H),2.85-2.90 (m, 1 H), 2.36-2.54 (m, 1 H), 1.26-2.05 (m, 16 H), 0.94 (d,J=6.3 Hz, 3 H), 0.57 (s, 3 H).

Example 1

Production of Compound No. 1144 ##STR17##

The aldehyde [A] (232 mg), which had been prepared by theabove-mentioned method from vitamin D₂, and ketone [B] (52 mg) weredissolved in 3 ml of ethanol, the resultant solution was stirredovernight at room temperature after the addition of KOH (54 mg). Thereaction mixture was extracted twice with ethyl acetate after ethylacetate and 1N hydrochloric acid were added. Both the organic layerswere combined, and they were washed with a saturated sodium bicarbonateaqueous solution, dried and concentrated. The residue was purified withsilica gel column chromatography (hexane: ethyl acetate=100:3 to 100:7)to separate two spots each containing [C]. Yield: 51 mg and 55 mg (106mg in total, 38%). Colorless oils. The product (51 mg) corresponding tothe upper spot on the TLC out of the obtained [C] was dissolved in amixed solvent of 0.5 ml of methylene chloride and 2.5 ml ofacetonitrile, and the resultant solution was cooled with ice. To thesolution was added lithium tetrafluoroborate (21 mg), and further wasadded dropwise 67.2 ml of 1N sulfuric acid solution in acetonitrile, andthe mixture was stirred for 1 hr as it was. The reaction mixture wasextracted twice with ethyl acetate after the addition of a saturatedsodium bicarbonate aqueous solution. Both the organic layers werecombined, and they were washed with brine, dried and concentrated. Theresidue was purified by HPLC (column: ODS, solvent: acetonitrile/water)to obtain the objective products, which were a compound having higherpolarity (Compound No. 1144a) and that having a lower polarity (CompoundNo. 1144b), respectively. These are optical isomers originated from thecarbon atom at the 20-position and the asymmetric carbon of the addedketone [B].

Further, the product (55 mg) corresponding to the lower spot on the TLCout of the obtained [C] was subjected to the deprotection reaction andpurification process similar to those mentioned above, and the objectiveproducts consisting of a compound having a higher polarity (Compound No.1144c) and that having a lower polarity (Compound No. 1144d) wereobtained. These are optical isomers originated from the carbon atom atthe 20-position and the asymmetric carbon of the added ketone [B].

[Compound No. 1144a]

¹ H NMR (CDCl₃) δ: 6.62 (dt, J=2.5, 10.7 Hz, 1 H), 6.35 (d, J=11.2 Hz, 1H), 6.00 (d, J=11.1 Hz, 1 H), 5.33 (s, 1 H), 4.43 (br., 1 H), 4.99 (s, 1H), 4.22 (br., 1 H), 2.78-2.82 (m, 1 H), 2.56-2.65 (m, 2 H), 2.10-2.45(m, 4 H), 1.85-2.06 (m, 4 H), 1.48-1.65 (m, 10 H), 1.15-1.46 (m, 5 H),0.97 (d, J=6.8 Hz, 3 H), 0.92 (t, J=7.3 Hz, 3 H), 0.43 (s, 3 H).

MS m/e=477.3 [M+Na]⁺.

[Compound No. 1144b]

¹ H NMR (CDCl₃) δ: 6.53 (dt, J=2.5,10.7 Hz, 1 H), 6.37 (d, J=11.1 Hz, 1H), 6.01 (d, J=11.4 Hz, 1 H), 5.32 (s, 1 H), 4.98 (s, 1 H), 4.43 (br., 1H), 4.24 (br., 1 H), 2.81-2.86 (m, 1 H), 2.58-2.68 (m, 2 H), 2.28-2.43(m, 3 H), 2.07-2.18 (m, 1 H), 1.64-2.05 (m, 8 H), 1.37-1.59 (m, 10 H),1.11-1.19 (m, 1 H), 1.06 (d, J=6.6 Hz, 3 H), 0.93 (t, J=7.4 Hz, 3 H),0.57 (s, 3 H).

MS m/e=477.3 [M+Na]⁺.

[Compound No. 1144c]

¹ H NMR (CDC1₃) δ: 6.63 (d, J=10.4 Hz, 1 H), 6.36 (d, J=11.2 Hz, 1 H),6.00 (d, J=11.2 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (br., 1 H),4.22 (br., 1 H), 2.79-2.84 (m, 1 H), 2.57-2.66 (m, 2 H), 2.10-2.43 (m, 4H), 1.79-2.07 (m, 4 H), 1.16-1.70 (m, 15 H), 0.97 (d, J=6.8 Hz, 3 H),0.94 (t, J=7.3 Hz, 3 H), 0.41 (s, 3 H).

MS m/e=477.3 [M+Na]⁺.

[Compound No. 1144d]

¹ H NMR (CDCl₃) δ: 6.54 (dt, J=2.5, 10.6 Hz, 1 H), 6.37 (d, J=11.2 Hz, 1H), 6.01 (d, J=11.2 Hz, 1 H), 5.32 (s, 1 H), 4.98 (s, 1 H), 4.43 (br., 1H), 4.23 (br., 1 H), 2.81-2.86 (m, 1 H), 2.57-2.67 (m, 2 H), 2.28-2.44(m, 3 H), 2.04-2.18 (m, 1 H), 1.26-2.01 (m, 19 H), 1.06 (d, J=6.6 Hz, 3H), 0.94 (t, J=7.3 Hz, 3 H), 0.57 (s, 3 H).

MS m/e=477.3 [M+Na]⁺.

Example 2

Production of Compound No. 1104

The objective compound was produced in the same way as in Example 1using the corresponding ketone.

¹ H NMR (CDC1₃) δ: 6.57 (d, J=11 Hz, 1 H), 6.42 (d, J=10 Hz,1 H), 5.87(d, J=11 Hz,1 H), 5.12 (m, 1 H), 4.98 (m, 1 H), 4.50 (m, 1 H), 4.23 (m,1 H), 1.10-2.89 (m, 27 H), 1.02 (d, J=6 Hz,3 H), 0.60 (s, 3 H).

Example 3

Production of Compound No. 1105a

The objective compound was produced in the same way as in Example 1using the corresponding aldehyde and ketone.

¹ H NMR (CDC1₃) δ: 6.67-6.70 (m, 1 H), 6.38 (d, J=10 Hz,1 H), 6.02 (d,J=11 Hz, 1 H), 5.33 (m, 1 H), 5.00 (s, 1 H), 4.43 (m, 1 H), 4.23 (m, 1H), 1.23-2.85 (m, 29 H), 0.94 (d ,J=6 Hz, 3 H), 0.55 (s, 3 H).

Example 4

Production of Compound No. 1106

The objective compound was produced in the same way as in Example 1using the corresponding aldehyde and ketone.

¹ H NMR (CDCl₃) δ: 6.61 (m, 1 H), 6.38 (d, J=11 Hz, 1 H), 6.02 (d, J=11Hz, 1 H), 5.33 (m , 1 H), 5.00 (s, 1 H), 4.43 (m, 1 H), 4.23 (m, 1 H),1.22-2.85 (m, 31 H), 0.95 (d, J=6 Hz,3 H), 0.54 (s, 3 H).

Example 5

Production of Compound No. 1126

The objective compounds were produced in the same way as in Example 1using the corresponding ketone. After the deprotection reaction, thecrude product was purified by HPLC (column: ODS, solvent:acetonitrile/water) to obtain the objective products (four isomers).Below, data are shown in the order of retention times from the shortestone. The products are optical isomers originated from the carbon atom atthe 20-position and the asymmetric carbon of the added ketone.

[Compound No. 1126a]

¹ H NMR (CDCl₃) δ: 6.63 (d, J=10.7 Hz, 1 H), 6.35 (d, J=11.2 Hz, 1 H),6.00 (d, J=11.2 Hz, 1 H), 5.33 (s, 1 H), 4.99 (s, 1 H), 4.43 (br., 1 H),4.23 (br., 1 H), 1.00-3.00 (m, 21 H), 1.25 (s, 3 H), 0.96 (d, J=6.8 Hz,3 H), 0.44 (s, 3 H).

[Compound No. 1126b]

¹ H NMR (CDCl₃) δ: 6.54 (d, J=10.6 Hz,1 H),6.37 (d, J=11.2 Hz,1 H), 6.01(d, J=11.2Hz,1 H), 5.32 (s, 1 H), 4.98 (s, 1 H), 4.43 (br., 1 H), 4.23(br., 1 H), 0.88-2.62 (m, 20 H), 1.26 (s, 3 H), 1.06 (d, J=6.6 Hz,3 H),0.58 (s, 3 H). [Compound No. 1126c]

¹ H NMR (CDC1₃) δ: 6.64 (dd, J=2.4, 10.8 Hz, 1 H), 6.36 (d, J=11.2 Hz, 1H), 6.00 (d, J=11.5 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (br., 1H), 4.23 (br., 1 H), 2.79-2.82 (m, 1 H), 1.21-2.79 (m, 26 H), 0.97 (d,J=6.6 Hz, 3 H), 0.41 (s, 3 H).

[Compound No. 1126d]

¹ H NMR (CDC1₃) δ: 6.56 (d, J=10.2 Hz, 1 H), 6.37 (d, J=11.2 Hz,1 H),6.01 (d, J=12.2 Hz,1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.44 (m, 1 H),4.23 (m, 1 H), 2.81-2.87 (m, 1 H), 1.13-2.62 (m, 20 H), 1.27 (s, 3 H),1.07 (d, J=6.6 Hz,3 H), 0.58 (s, 3 H).

Example 6

Production of Compound No. 1129

The objective compounds were produced in the same way as in Example 1using the corresponding ketone. After the aldol reaction, the reactionproduct was divided into two groups of compounds having a lower polarityand a higher polarity, respectively by silica gel column chromatography,both the groups of compounds were subjected to the deprotectionreaction, the resultant two crude products were each fractionallypurified by HPLC (column: ODS, solvent: acetonitrile/water). Thus, eachgroup obtained a pair of objective products having a lower polarity anda higher polarity. The products are optical isomers originated from thecarbon atom at the 20-position and the asymmetric carbon of the addedketone.

[Compound No. 1129a] (lower polarity after aldol reaction and higherpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 6.37 (d, J=11.1 Hz, 2 H), 6.00 (d, J=11.5 Hz, 1 H),5.32 (t, J=1.8 Hz, 1 H), 4.99 (s, 1 H), 4.41-4.45 (m, 1 H), 4.19-4.25(m, 1 H), 2.78-2.83 (m, 2 H), 2.59 (dd, J=3.8, 13.7 Hz, 1 H), 2.17-2.35(m, 3 H) 1.85-2.11 (m, 7 H), 1.19-1.80 (m, 16 H), 0.94 (d, J=6.6 Hz, 3H), 0.39 (s, 3 H).

[Compound No. 1129b] (lower polarity after aldol reaction and lowerpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=10.5 Hz, 1 H), 6.20 (d, J=10.0 Hz, 1 H),6.02 (d, J=11.6 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (m, 1 H),4.08-4.24 (m, 1 H), 3.75 (br., 1 H), 2.81-2.88 (m, 2 H), 1.23-2.72 (m,20 H), 1.25 (s, 3 H), 1.02 (d, J=6.6 Hz, 3 H), 0.59 (s, 3 H).

[Compound No. 1129c] (higher polarity after aldol reaction and higherpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 6.36 (d, J=11.2 Hz, 2 H), 6.01 (d, J=11.2 Hz, 1 H),5.33 (t, J=1.7 Hz, 1 H), 4.99 (s, 1 H), 4.41-4.46 (m, 1 H), 4.19-4.26(m, 1 H), 2.78-2.87 (m, 2 H), 2.59 (dd, J=3.5, 13.5 Hz, 1 H), 2.11-2.37(m, 3 H), 1.86-2.06 (m, 7 H), 1.15-1.78 (m, 16 H), 0.92 (d, J=6.6 Hz, 3H), 0.46 (s, 3 H).

[Compound No. 1129d] (higher polarity after aldol reaction and lowerpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 6.37 (d, J=11.2 Hz,1 H), 6.29(d, J=9.6 Hz, 1 H), 6.03(d, J=11.5 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.42 (m, 1 H), 4.23(m, 1H), 3.71 (br., 1 H), 2.81-2.86 (m, 2 H), 1.23-2.57 (m, 20 H), 1.30(s, 1 H), 1.04 (d, J=6.6 Hz, 3 H), 0.58 (s, 3 H).

Example 7

Production of Compound No. 1148

The objective compounds were produced in the same way as in Example 1using the corresponding ketone. After the aldol reaction, the reactionproduct was divided into two groups of compounds having a lower polarityand a higher polarity, respectively by silica gel column chromatography,both the groups of compounds were subjected to the deprotectionreaction, the resultant two crude products were each fractionallypurified by HPLC (column: ODS, solvent: acetonitrile/water). Thus, eachgroup obtained a pair of objective products having a lower polarity anda higher polarity. The products are optical isomers originated from thecarbon atom at the 20-position and the asymmetric carbon of the addedketone.

[Compound No. 1148a] (lower polarity after aldol reaction and higherpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 6.63 (dt, J=2.3, 10.4 Hz, 1 H), 6.36 (d, J=11.2 Hz, 1H), 6.00 (d, J=11.1 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (br., 1H), 4.23 (br., 1 H), 2.79-2.83 (m, 1 H), 2.52-2.66 (m, 2 H), 2.11-2.44(m, 4 H), 1.78-2.07 (m, 5 H), 1.16-1.70 (m, 16 H), 0.97 (d, J=6.6 Hz, 3H), 0.92 (t, J=6.9 Hz, 3 H), 0.41 (s, 3 H).

MS m/e=469.0 [M+1]⁺.

[Compound No. 1148b] (lower polarity after aldol reaction and lowerpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 6.54 (dt, J=2.6, 10.2 Hz, 1 H), 6.37 (d, J=10.1 Hz, 1H), 6.01 (d, J=11.6 Hz, 1 H), 5.32 (d, J=1.7 Hz,1 H), 4.98 (s, 1 H),4.43 (br., 1 H), 4.23 (br., 1 H), 2.81-2.86 (m, 1 H), 2.57-2.66 (m, 2H), 2.28-2.49 (m, 4 H), 2.07-2.18 (m, 1 H), 1.13-2.00 (m, 20 H), 1.06(d, J=6.6 Hz, 3 H), 0.92 (t, J=6.9 Hz, 3 H), 0.58 (s, 3 H).

MS m/e=469.6 [M+1]⁺.

[Compound No. 1148c] (higher polarity after aldol reaction and higherpolarity by HPLC separation)

¹ H NMR (CDCl3) δ: 6.61 (dt, J=2.5, 10.4 Hz, 1 H), 6.36 (d, J=11.2 Hz, 1H), 6.01 (d, J=11.6 Hz, 1 H), 5.33 (d, J=1.5 Hz,1 H), 4.99 (s, 1 H),4.44 (br., 1 H), 4.23 (br., 1 H), 2.78-2.83 (m, 1 H), 2.55-2.64 (m, 2 H)2.05-2.46 (m, 4 H), 1.79-2.02 (m, 5 H), 1.15-1.65 (m, 16 H), 0.97 (d,J=6.6 Hz, 3 H), 0.89 (t, J=6.9 Hz, 3 H), 0.44 (s, 3 H).

MS m/e=469.3 [M+1]⁺.

[Compound No. 1148d] (higher polarity after aldol reaction and lowerpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 6.53 (dt, J=2.3, 10.4 Hz, 1 H), 6.37 (d, J=11.2 Hz, 1H), 6.01 (d, J=11.7 Hz, 1 H), 5.33 (d, J=1.7 Hz,1 H), 4.99 (s, 1 H),4.43 (br., 1 H), 4.23 (br., 1 H), 2.81-2.87 (m, 1 H), 2.52-2.67 (m, 2H), 2.28-2.43 (m, 4 H), 2.04-2.18 (m, 1 H), 1.65-2.01 (m, 7 H),1.11-1.57 (m, 13 H), 1.06 (d, J=6.6 Hz, 3 H), 0.91 (t, J=6.9 Hz, 3 H),0.58 (s, 3 H).

MS m/e=469.0 [M+1]⁺.

Example 8

Production of Compound No. 1152

The objective compounds were produced in the same way as in Example 1using the corresponding ketone. After the aldol reaction, the reactionproduct was divided into two groups of compounds having a lower polarityand a higher polarity, respectively by silica gel column chromatography,both the groups of compounds were subjected to the deprotectionreaction, the resultant two crude products were each fractionallypurified by HPLC (column: ODS, solvent: acetonitrile/water). Thus, eachgroup obtained a pair of objective products having a lower polarity anda higher polarity. The products are optical isomers originated from thecarbon atom at the 20-position and the asymmetric carbon of the addedketone.

[Compound No. 1152a] (lower polarity after aldol reaction and higherpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 7.24-7.32 (m, 3 H), 7.15-7.18 (m, 2 H), 6.66 (d,J=10.4 Hz, 1 H), 6.35 (d, J=10.9 Hz, 1 H), 5.99 (d, J=11.4 Hz, 1 H),5.32 (s, 1 H), 4.98 (s, 1 H), 4.43 (br., 1 H), 4.22 (br., 1 H), 2.83 (d,J=1.2 Hz, 2 H), 2.77-2.88 (m, 1 H), 2.50-2.62 (m, 2 H), 2.13-2.34 (m, 4H), 1.78-2.07 (m, 5 H), 1.14-1.69 (m, 12 H), 0.94 (d, J=6.8 Hz, 3 H),0.39 (s, 3 H).

MS m/e=517.3 [M+1]⁺.

[Compound No. 1152b] (lower polarity after aldol reaction and lowerpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 7.20-7.32 (m, 3 H), 7.15-7.18 (m, 2 H), 6.57 (dt,J=2.6, 10.6 Hz, 1 H), 6.37 (d, J=11.2 Hz, 1 H), , 6.00 (d, J=11.1 Hz, 1H), 5.31 (s, 1 H) 4.98 (s, 1 H), 4.43 (br., 1 H), 4.22 (br., 1 H), 2.82(d, J=2.1 Hz, 2 H), 2.76-2.86 (m, 1 H), 2.50-2.62 (m, 2 H), 2.12-2.40(m, 4 H), 1.88-2.06 (m, 4 H), 1.66-1.83 (m, 4 H), 1.11-1.57 (m, 9 H),1.04 (d, J=6.6 Hz, 3 H), 0.56 (s, 3 H).

MS m/e=517.3 [M+1]⁺.

[Compound No. 1152c] (higher polarity after aldol reaction and higherpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 7.21-7.27 (m, 3 H), 7.10-7.13 (m, 2 H), 6.63 (d,J=10.6 Hz, 1 H), 6.37 (d, J=11.2 Hz, 1 H), 6.02 (d, J=11.4 Hz, 1 H),5.33 (d, J=1.7 Hz, 1 H), 5.00 (s, 1 H), 4.44 (br., 1 H), 4.23 (br., 1H), 2.84 (s, 2 H), 2.80-2.84 (m, 1 H), 2.50-2.64 (m, 2 H), 2.12-2.35 (m,4 H), 1.78-2.07 (m, 5 H), 1.20-1.70 (m, 12 H), 0.95 (d, J=6.8 Hz, 3 H),0.39 (s, 3 H).

MS m/e=517.3 [M+1]⁺.

[Compound No. 1152d] (higher polarity after aldol reaction and lowerpolarity by HPLC separation)

¹ H NMR (CDCl₃) δ: 7.22-7.32 (m, 3 H), 7.10-7.16 (m, 2 H), 6.55 (dt,J=2.3, 10.7 Hz, 1 H), 6.38 (d, J=11.4 Hz, 1 H), 6.02 (d, J=11.2 Hz, 1H), 5.34 (d, J=1.7 Hz, 1 H), 5.00 (s, 1 H), 4.44 (br., 1 H), 4.24 (br.,1 H), 2.82 (d, J=2.2 Hz, 2 H), 2.77-2.88 (m, 1 H), 2.54-2.65 (m, 2 H),2.28-2.39 (m, 2 H), 2.13-2.25 (m, 2 H), 1.87-2.08 (m, 4 H), 1.64-1.84(m, 4 H), 1.13-1.58 (m, 9 H), 1.05 (d, J=6.6 Hz, 3 H), 0.57 (s, 3 H).

MS m/e=517.2 [M+1]⁺.

Example 9

Production of Compound No. 1156

The objective compounds were produced in the same way as in Example 1using the corresponding ketone. After the aldol reaction, the reactionproduct was subjected to the deprotection reaction, the crude productwas fractionally purified by HPLC (column: ODS, solvent:acetonitrile/water) to obtain a pair of objective products having alower polarity and a higher polarity. The products are optical isomersoriginated from the asymmetric carbon of the added ketone.

[Compound No. 1156a] (having lower polarity)

¹ H NMR (CDCl₃) δ: 6.43 (m, 1 H), 6.37 (d, J=11 Hz, 1 H), 6.01 (d, J=11Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (m, 1 H), 4.23 (m, 1 H),3.55-3.64 (m, 2 H), 1.28-2.86 (m, 27 H), 1.06 (m, 3 H), 0.58 (s, 3 H).

[Compound No. 1156b] (having higher polarity)

¹ H NMR (CDCl₃) δ: 6.43 (m, 1 H), 6.37 (d, J=11 Hz, 1 H), 6.01 (d, J=11Hz,1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (m, 1 H), 4.23 (m, 1 H),3.55-3.64 (m, 2 H), 1.28-2.86 (m, 27 H), 1.09 (m, 3 H), 0.58 (s, 3 H).

Example 10

Production of Compound No. 2101

The objective compound was produced in the same way as in Example 1using the corresponding ketone.

¹ H NMR (CDCl₃) δ: 7.56 (m, 1 H), 6.45 (d, J=11 Hz, 1 H), 6.35-6.40 (m,2 H), 6.01 (d, J=11 Hz, 1 H), 5.32 (s, 1 H), 4.98 (d, J=10 Hz, 1 H),4.98 (s, 1 H), 4.42 (m, 1 H), 4.23 (m, 1 H), 3.20 (m, 1 H), 1.13-2.86(m, 19 H), 1.09 (d, J=6 Hz, 3 H), 0.59 (s, 3 H).

Example 11

Production of compound No. 2104

The objective compounds were produced in the same way as in Example 1using the corresponding ketone. After the aldol reaction, the reactionproduct was subjected to the deprotection reaction, the crude productwas fractionally purified by HPLC (column: ODS, solvent:acetonitrile/water) to obtain a pair of objective products having alower polarity and a higher polarity. The products are optical isomersoriginated from the carbon atom at the 20-position.

[Compound No. 2104a] (having lower polarity)

¹ H NMR (CDCl₃) δ: 7.17 (s, 1 H), 6.42 (d, J=11.1 Hz, 1 H), 6.37 (d,J=11.1 Hz, 1 H), 6.00 (d, J=11.1 Hz, 1 H), 5.32 (s, 1 H), 4.98 (s, 1 H),4.43 (br., 1 H), 4.24 (br., 1 H), 1.85 (s, 3 H), 1.08 (d, J=6.5 Hz, 3H), 1.00-3.00 (m, 19 H), 0.58 (s, 3 H).

MS m/e=421.1 [M-1]⁺.

[Compound No. 2104b] (having higher polarity)

¹ H NMR (CDCl₃) δ: 7.17 (s, 1 H), 6.53 (d, J=11.6 Hz, 1 H), 6.36 (d,J=11.2 Hz, 1 H), 6.00 (d, J=11.2 Hz, 1 H), 5.33 (s, 1 H), 4.99 (s, 1 H),4.43 (br., 1 H), 4.23 (br., 1 H), 1.85 (s, 3 H), 1.00-3.00 (m, 19 H),1.00 (d, J=6.6 Hz, 3 H), 0.42 (s, 3 H). MS m/e=444.9[M+23]⁺.

Example 12

Production of Compound No. 1130 ##STR18##

Under argon atmosphere, 1.15 ml of 1.66 M butyllithium solution inhexane was added to a solution of diisopropylamine (212 mg) in THF,which had been cooled to 0 °C., and the mixture was stirred for 15 min.After the mixture was cooled to -78 °C., a solution of ketone [E] (285mg) in THF was added, and the resultant mixture was stirred for 20 min.To the reaction mixture was added a solution of the aldehyde [D] (285mg), which had been produced in Reference Example 2, in THF, and theresultant mixture was stirred for 1 hr. The reaction was stopped byadding 15 ml of a saturated ammonium chloride solution, and then thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate anhydride andconcentrated to obtain crude [F].

The obtained [F] was dissolved in dimethylformamide. To the obtainedsolution were added dimethylaminopyridine (612 mg) and methanesulfonylchloride (160 μl) under argon atmosphere at 0° C. The temperature of themixture was elevated to 50° C., and the mixture was stirred overnight.Then, brine was added to the reaction mixture, and organic matters wereextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate anhydride and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1)to obtain [G] (about 560 mg).

Under argon atmosphere, triphenylphosphine (35.3 mg) andtris(dibenzylideneacetone)palladium(0)-chloroform adduct (22.7 mg) weredissolved in 2 ml of toluene and 2 ml of diisopropylethylamine, and theobtained solution was stirred at room temperature for 20 min. To thissolution was added a solution of [G] (90.3 mg) and [H] (165 mg) in amixed solvent of toluene-diisopropylethylamine, and the resultantmixture was warmed up to 120° C. and stirred for 2 hr. The reactionmixture was allowed to cool down, filtered and concentrated. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=7:1) to obtain [I] (113 mg).

The obtained [I] was dissolved in a mixed solvent of acetonitrile:methylene chloride=3:1, and the resultant solution was cooled to 0° C.Lithium tetrafluoroborate (40 mg) was added, and to the resultantmixture was added dropwise little by little an acetonitrile-dilutedsulfuric acid. When the raw material had disappeared, a saturated sodiumbicarbonate aqueous solution was added, and the reaction mixture wasextracted with methylene chloride. The organic layer was washed withbrine and dried over sodium sulfate anhydride. The solution wasevaporated, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1), and subsequently purified byHPLC (column: ODS, solvent:acetonitrile/water) to obtain a pair of theobject products having lower polarity and higher polarity. They areisomers originated from an asymmetric carbon of the added ketone [E].

[Compound 1130a] (having lower polarity)

¹ H NMR (CDCl₃) δ: 6.51-6.57 (m, 1 H), 6.38 (d, J=11 Hz, 1 H), 6.02 (d,J=11 Hz, 1 H), 5.33 (d, J=1.3 Hz, 1 H), 5.00 (d, J=1.3 Hz, 1 H),4.41-4.45 (m, 1 H), 4.20-4.26 (m, 1 H), 3.70 (br., 1 H), 2.77-2.84 (m, 2H), 2.57-2.63 (m, 1 H), 1.23-2.35 (m, 24 H), 1.31 (s, 3 H), 0.94 (d,J=6.6 Hz, 3 H).

[Compound 1130a] (having higher polarity) ¹ H NMR (CDCl₃) δ: 6.51-6.57(m, 1 H), 6.38 (d, J=11 Hz, 1 H), 6.02 (d, J=11 Hz, 1 H), 5.33 (d, J=1.3Hz, 1 H), 5.00 (d, J=1.3 Hz, 1 H), 4.41-4.45 (m, 1 H), 4.20-4.26 (m, 1H), 3.70 (br., 1 H), 2.77-2.84 (m, 2 H), 2.57-2.63 (m, 1 H), 1.23-2.35(m, 24 H), 1.31 (s, 3 H), 0.94 (d, J=6.6 Hz, 3 H).

Example 13

Production of Compound 1101

The objective compound was produced in the same way as in Example 12using the corresponding aldehyde and ketone. ¹ H NMR (CDCl₃) δ: 6.37 (d,J=10.5 Hz, 2 H), 6.02 (d, J=11.2 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H),4.31-4.43 (m, 1 H), 4.2-4.3 (m, 1 H), 1.2-2.9 (m, 25 H), 1.05 (d, J=6.6Hz, 3 H), 0.58 (s, 3 H).

Example 14

Production of Compound 1102

The objective compound was produced in the same way as in Example 12using the corresponding ketone.

¹ H NMR (CDCl₃) δ: 6.56-6.64 (m, 1 H), 6.38 (d, J=11 Hz, 1 H), 6.01 (d,J=11 Hz, 1 H), 5.33 (s, 1 H), 5.00 (s, 1 H), 4.41-4.46 (br., 1 H),4.21-4.27 (br., 1 H), 2.80-2.85 (m, 1 H), 2.56-2.63 (m, 1 H), 1.20-2.80(m, 25 H), 0.95 (d, J=6.3 Hz, 3 H), 0.55 (s, 3 H).

Example 15

Production of Compound 1103

The objective compound was produced in the same way as in Example 12using the corresponding aldehyde and ketone.

¹ H NMR (CDCl₃) δ: 6.53 (t, J=7.6 Hz, 1 H), 6.37 (d, J=11.2 Hz, 1 H),6.02 (d, J=11.5 Hz, 1 H), 5.33 (s, 1 H), 5.00 (s, 1 H), 4.41-4.46 (m, 1H), 4.22-4.24 (m, 1 H), 2.70-2.85 (m, 1 H), 1.1-2.7 (m, 28 H), 0.96 (d,J=6.3 Hz, 3 H), 0.54 (s, 3 H).

Example 16

Production of Compound 1107

The objective compound was produced in the same way as in Example 12using the corresponding aldehyde and ketone.

¹ H NMR (CDCl₃) δ: 6.41 (d, J=10.6 Hz, 1 H), 6.37 (d, J=10.6 Hz, 1 H),6.01 (d, J=11.2 Hz, 1 H), 5.32 (s, 1 H), 4.98 (s, 1 H), 4.40-4.45 (m, 1H), 4.19-4.25 (m, 1 H), 2.80-2.86 (m, 1 H), 1.08-2.61 (m, 26 H), 1.02(d, J=6.6 Hz, 3 H), 0.59 (s, 3 H).

Example 17

Production of Compound 1110

The objective compounds were produced in the same way as in Example 12using the corresponding aldehyde and ketone. After the deprotectionreaction, the crude product was fractionally purified by HPLC (column:ODS, solvent: acetonitrile/water) to obtain a pair of objective productshaving a lower polarity and a higher polarity. The products are opticalisomers originated from the asymmetric carbon of the added ketone.

[Compound No. 1110a] (having lower polarity)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 2 H), 6.01 (d, J=11 Hz, 1 H), 5.32(s, 1 H), 4.99 (s, 1 H), 4.43 (br., 1 H), 4.22-4.24 (br., 1 H),2.80-2.85 (m, 1 H), 2.56-2.69 (m, 1 H), 1.3-2.8 (m, 22 H), 1.13 (d, J=7Hz, 3 H), 1.06 (d, J=6.6 Hz, 3 H), 0.58 (s, 3 H).

[Compound No. 1110b] (having higher polarity)

¹ H NMR (CDCl₃) δ: 6.39 (d, J=10.3 Hz, 1 H), 6.38 (d, J=11.9 Hz, 1 H),6.00 (d, J=11.5 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (s, 1 H),4.24 (s., 1 H), 2.80-2.86 (m, 1 H), 1.3-2.8 (m, 23 H), 1.14 (d, J=6.9Hz, 3 H), 1.05 (d, J=6.6 Hz, 3 H), 0.57 (s, 3 H).

Example 18

Production of Compound 1112

The objective compounds were produced in the same way as in Example 12using the corresponding aldehyde and ketone. After the deprotectionreaction, the crude product was fractionally purified by HPLC (column:ODS, solvent: acetonitrile/water) to obtain a pair of objective productshaving a lower polarity and a higher polarity. The products are opticalisomers originated from the asymmetric carbon of the added ketone.

[Compound No. 1112a] (having lower polarity)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 1 H), 6.01 (d, J=11 Hz, 1 H), 5.32(s, 1 H), 4.99 (s, 1 H), 4.43 (br., 1 H), 4.23 (br., 1 H), 2.81-2.86 (m,1H), 1.30-2.80 (m, 25 H), 1.04 (d, J=7 Hz, 3 H), 0.96 (t, J=7 Hz, 3 H),0.57 (s, 3 H).

[Compound No. 1112b] (having higher polarity)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 1 H), 6.01 (d, J=11 Hz, 1 H), 5.32(s, 1 H), 4.99 (s, 1 H), 4.43 (br., 1 H), 4.23 (br., 1 H), 2.81-2.86 (m,1H), 1.30-2.80 (m, 25 H), 1.04 (d, J=7 Hz, 3 H), 0.96 (t, J=7 Hz, 3 H),0.57 (s, 3 H).

Example 19

Production of Compound 1116

The objective compound was produced in the same way as in Example 12using the corresponding aldehyde and ketone.

¹ H NMR (CDCl₃) δ: 6.41 (d, J=10.6 Hz, 1 H), 6.37 (d, J=9.6 Hz, 1 H),6.01 (d, J=11.2 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (s, 1 H),4.21 (s, 1 H), 1.2-2.9 (m, 23 H), 1.07 (s, 6 H), 1.05 (d, J=5Hz, 3 H),0.58 (s, 3H).

Example 20

Production of Compound 1127

The objective compounds were produced in the same way as in Example 12using the corresponding ketone. After the coupling reaction with anene-yne compound, the crude product was purified by silica gel columnchromatography to separate a pair products having a lower polarity and ahigher polarity. Each of them were subjected to deprotection reaction toobtain the objective products. They are optical isomers originated fromthe asymmetric carbon of the added ketone.

[Compound No. 1127a] (obtained from the lower-polarity fraction ofsilica gel column chromatography)

¹ H NMR (CDCl₃) δ: 6.37 (d, J=11.2 Hz, 1 H), 6.29(d, J=9.6 Hz, 1 H),6.03 (d, J=11.5 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.42 (m, 1 H),4.23 (m, 1 H), 3.71 (br., 1 H), 2.81-2.86 (m, 2 H), 1.23-2.57 (m, 20 H),1.30 (s, 1 H), 1.04 (d, J=6.6 Hz, 3 H), 0.58 (s, 3 H).

[Compound No. 1127b] (obtained from the higher-polarity fraction ofsilica gel column chromatography)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=10.5 Hz, 1 H), 6.20 (d, J=10.0 Hz, 1 H),6.02 (d, J=11.6 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (m, 1 H),4.08-4.24 (m, 1 H), 3.75 (br., 1 H), 2.81-2.88 (m, 2 H), 1.23-2.72 (m,20 H), 1.25 (s, 3 H), 1.02 (d, J=6.6 Hz, 3 H), 0.59 (s, 3 H).

Example 21

Production of Compound 1128

The objective compounds were produced in the same way as in Example 12using the corresponding aldehyde and ketone. After the deprotectionreaction, the crude product was fractionally purified by HPLC (column:ODS, solvent: acetonitrile/water) to obtain a pair of objective productshaving a lower polarity and a higher polarity. The products are opticalisomers originated from the asymmetric carbon of the added ketone.

[Compound No. 1128a] (having a lower polarity)

¹ H NMR (CDCl₃) δ: 6.72 (t, J=7.6 Hz, 1 H), 6.38 (d, J=11.2 Hz, 1 H),6.02 (d, J=11.2 Hz, 1 H), 5.33 (s, 1 H), 5.00 (s, 1 H), 4.44 (br., 1 H),4.23 (br, 1 H), 2.80-2.85 (m, 1 H), 1.15-2.62 (m, 24 H), 1.27 (s, 3 H),0.96 (d, J=6.3Hz, 3 H), 0.55 (s, 3 H).

[Compound No. 1128b] (having a higher polarity)

¹ H NMR (CDCl₃) δ: 6.72 (t, J=7.6 Hz, 1 H), 6.38 (d, J=11.2 Hz, 1 H),6.02 (, J=11.2 Hz d, 1 H), 5.33 (s, 1 H), 5.00 (s, 1 H), 4.44 (br., 1H), 4.23 (br., 1 H), 2.80-2.85 (m, 1 H), 1.15-2.62 (m, 24 H), 1.27 (s, 3H), 0.96 (d, J=6.3 Hz, 3 H), 0.55 (s, 3 H).

Example 22

Production of Compound 1131

The objective compounds were produced in the same way as in Example 12using the corresponding aldehyde and ketone. After the deprotectionreaction, the crude product was fractionally purified by HPLC (column:ODS, solvent: acetonitrile/water) to obtain a pair of objective productshaving a lower polarity and a higher polarity. The products are opticalisomers originated from the asymmetric carbon of the added ketone.

[Compound No. 1131a] (having lower polarity)

¹ H NMR (CDCl₃) δ: 6.47-6.50 (m, 1 H), 6.38 (d, J=11.2 Hz, 1 H), 6.02(d, J=11.2 Hz, 1 H), 5.33 (s, 1 H), 5.00 (s, 1 H), 4.43 (m, 1 H), 4.23(m, 1H), 3.71 (br., 1 H), 2.81 (m, 2 H), 2.58 (m, 1 H), 1.23-2.35 (m, 24H), 1.30 (s, 3 H), 0.96 (d, J=6.3 Hz, 3 H), 0.55 (s, 3 H).

[Compound No. 1131b] (having higher polarity)

¹ H NMR (CDCl₃) δ: 6.47-6.50 (m, 1 H), 6.38 (d, J=11.2 Hz, 1 H), 6.02(d, J=11.2 Hz, 1 H), 5.33 (s, 1 H), 5.00 (s, 1 H), 4.43 (m, 1 H), 4.23(m, 1H), 3.71 (br., 1 H), 2.81 (m, 2 H), 2.58 (m, 1 H), 1.23-2.35 (m, 24H), 1.30 (s, 3 H), 0.96 (d, J=6.3 Hz, 3 H), 0.54 (s, 3 H).

Example 23

Production of Compound No. 1110c ##STR19##

The aldehyde [J] (213 mg), which had been obtained in Reference Example1, was dissolved in DMF, and the resultant solution was stirred for 3days at room temperature after the addition of DABCO (74 mg). Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried over sodiumsulfate anhydride. By evaporating, the solution gave aldehyde [K] inwhich the α-position of the formyl group of aldehyde [J] had beenepimerized. Subsequently, the obtained aldehyde [K] was treated in thesame way as in Example 12 by using the corresponding ketone. After thedeprotection reaction, the crude product was purified by HPLC (column:ODS, solvent: acetonitrile/water) to obtain the objective product.

¹ H NMR (CDCl₃) δ: 6.46 (d, J=10.2 Hz, 1 H), 6.37 (d, J=10.2 Hz, 1 H),6.00 (d, J=10.7 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.44 (br., 1 H),4.23 (br., 1 H), 2.77-2.86 (m, 1 H), 1.2-2.8 (m, 23 H), 1.14 (d, J=6.6Hz, 3 H), 0.95 (d, J=6.6 Hz, 3 H), 0.42 (s, 3 H).

Example 24

Production of Compound No. 1226 ##STR20##

Sodium borohydride (56.7 mg) was added to 6 ml of pyridine undernitrogen atmosphere, and the mixture was stirred for about 30 min at 70°C. Subsequently, the mixture was cooled to room temperature, and asolution prepared by dissolving [L] (335 mg) in 6 ml of pyridine wasadded using a syringe to the above-mentioned reductant solution, and theresultant mixture was stirred for about 1 hr at room temperature. Thereaction mixture was extracted with ethyl acetate after the addition of6N hydrochloric acid. The organic layer was washed with a saturatedsodium bicarbonate aqueous solution, dried and concentrated. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=3:1) to obtain [M]. This was treated for deprotection reactionaccording to the method of Example 1, and the crude product was purifiedby HPLC (column: ODS, solvent: acetonitrile/water) to obtain theobjective product.

¹ H NMR (CDCl₃) δ: 6.36 (d, J=11.1 Hz, 1 H), 6.03 (d, J=11.1 Hz, 1 H),5.34 (s, 1 H), 4.99 (s, 1 H), 1.00-3.00 (m, 24 H), 1.22 (s, 3 H), 0.95(d, J=5.9 Hz, 3 H), 0.56 (s, 3 H).

MS m/e=465.2 [M+23]⁺.

Example 25

Production of Compound No. 1401 ##STR21##

Under nitrogen atmosphere, 180 μl of 1.01M diisobutylaluminum hydridesolution was added dropwise to a methylene chloride solution of thecompound No. 1101 (34 mg) which had been cooled to -78° C., and themixture was stirred for 40 min. After stopping the reaction by slowlyadding 0.5 ml of a saturated sodium sulfate aqueous solution, 0.5 ml ofmethanol and 0.5 ml of 2N hydrochloric acid, and further ethyl acetateand magnesium sulfate were added, and the resultant mixture was stirredfor 30 min at room temperature. After filtration, the organic layer waswashed with brine and dried. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=1:1), and further purifiedby HPLC (column: ODS, solvent: acetonitrile/water) to obtain a pair ofthe objective products having a lower polarity and a higher polarity.They are optical isomers originated from the asymmetric carbon bound towhich the hydroxyl group formed by the reaction is bound.

[Compound No. 1401a] (having a lower polarity)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 1 H), 6.01 (d, J=11 Hz, 1 H), 5.35(d, J=10 Hz, 1 H), 5.32 (s, 1 H), 5.00 (s, 1 H), 4.42 (br., 1 H), 4.36(br., 1 H), 4.21-4.20 (m, 1 H), 2.82 (t-like, 1 H), 2.60 (d-like, 1 H),2.60 (d-like, 1 H), 1.2-2.4 (m, 23 H), 0.99 (d, J=7.4 Hz, 3 H), 0.57 (s,3 H).

[Compound No. 1401b] (having a higher polarity)

¹ H NMR (CDCl₃) δ: 6.37 (d, J=11 Hz, 1 H), 6.02 (d, J=11 Hz, 1 H), 5.35(d, J=10 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.43 (br., 1 H), 4.35(br., 1 H), 4.11-4.20 (m, 1 H), 2.82 (t-like, 1 H), 2.60 (d-like, 1 H),2.58 (d-like, 1 H), 1.2-2.4 (m, 23 H), 0.99 (d, J=7.4 Hz, 3 H), 0.57 (s,3 H).

Example 26

Production of Compound No. 1404

In the same way as in Example 25, the objective compounds were producedusing the corresponding ketone. After the reaction, a crude product wasfractionally purified by HPLC (column: ODS, solvent: acetonitrile/water)to obtain a pair of the objective products having a lower polarity and ahigher polarity. They are optical isomers originated from the asymmetriccarbon bound to which the hydroxyl group formed by the reaction isbound.

[Compound No. 1404a] (having a lower polarity)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 1 H), 6.02 (d, J=11 Hz, 1 H), 5.32(s, 1 H), 5.13 (d, J=10 Hz, 1 H), 5.00 (s, 1 H), 4.43 (m, 1 H), 4.23 (m,1 H), 4.08 (m, 1 H), 1.10-2.85 (m, 28 H), 0.97 (d, J=6 Hz, 3 H), 0.59(s, 3 H).

[Compound No. 1404b] (having a higher polarity)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 1 H), 6.00 (d, J=11 Hz, 1 H), 5.32(s, 1 H), 5.13 (d, J=10 Hz, 1 H), 5.00 (s, 1 H), 4.42 (m, 1 H), 4.22 (m,1 H), 4.06 (m, 1 H), 1.10-2.85 (m, 28 H), 0.98 (d, J=6 Hz, 3 H), 0.58(s, 3H).

Example 27

Production of Compound No. 1416

In the same way as in Example 25, the objective compounds were producedusing the corresponding ketone. After the reaction, a crude product wasfractionally purified by HPLC (column: ODS, solvent: acetonitrile/water)to obtain a pair of the objective products having a lower polarity and ahigher polarity. They are optical isomers originated from the asymmetriccarbon bound to which the hydroxyl group formed by the reaction isbound.

[Compound No. 1416a] (having a lower polarity)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 1 H), 6.01 (d, J=11 Hz, 1 H), 5.32(d, J=14 Hz, 1 H), 5.26 (d, J=12 Hz, 1 H), 4.99 (s, 1H), 4.42 (br., 1H), 4.23 (br., 1 H), 3.83 (s, 1 H), 2.82 (d, J=14 Hz, 1 H), 2.60 (d,J=16 Hz, 1 H), 1.1-2.4 (m, 22 H), 1.01 (s, 3 H), 0.98 (d, J=8 Hz, 3 H),0.79 (s, 3 H), 0.57 (s, 3 H).

[Compound No. 1416b] (having a higher polarity)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 1 H), 6.00 (d, J=11 Hz, 1 H), 5.32(s, 1 H), 5.30 (d, J=12 Hz, 1 H), 5.00 (s, 1 H), 4.43 (br., 1 H), 4.23(br., 1 H), 3.81 (s, 1 H), 2.83 (d, J=15 Hz, 1 H), 2.61 (d, J=15 Hz, 1H), 1.1-2.4 (m, 22 H), 0.97 (d, J=7 Hz, 3 H), 0.97 (s, 3 H), 0.84 (s,3H), 0.57 (s, 3 H).

Example 28

Production of Compounds No. 1426a and No. 1426b ##STR22##

The aldehyde [J], which had been produced in Reference Example 1, andketone [N] were converted into an aldol adduct-dehydration product [O]according to the process of Example 12. Under nitrogen atmosphere, [O](27 mg) was dissolved in 1 ml of ether, and the solution was cooled to-20° C. To the solution was added 0.4 ml of 0.15 M solution of Zn(BH₄)₂in ether (prepared from sodium hydrogen borate and zinc (II) chloride),and the mixture was stirred for 6.5 hr while the temperature was beingelevated slowly to room temperature. To the reaction mixture was added asaturated ammonium chloride aqueous solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,dried and concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=50:1 to 10:1) to obtain a pair ofalcohols [P] having a lower polarity and a higher polarity. The alcoholswere each allowed to couple with [H] according to a method same as inExample 12, and the reaction products were subjected to deprotectionreaction to obtain the objective products. They are optical isomersoriginated from the asymmetric carbon bound to which the hydroxyl groupformed by the reduction reaction of the ketone in this example is bound.

[Compound No. 1426a] (obtained from the fraction of a lower polarity ofsilica gel column chromatography)

¹ H NMR (CDCl₃) δ: 6.52 (d, J=11 Hz, 1 H), 6.00 (d, J=11 Hz, 1 H), 5.38(d, J=10 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.34 (br., 1 H), 4.23(br., 1 H), 3.91 (m, 1 H), 3.91 (br., 1 H), 2.83 (d, J=14 Hz, 1 H), 2.60(d, J=10 Hz, 1 H), 1.23-2.27 (m, 19 H), 1.27 (s, 3 H), 0.99 (d, J=6.5Hz, 3 H), 0.56 (s, 3 H).

[Compound No. 1426b] (obtained from the fraction of a higher polarity ofsilica gel column chromatography)

¹ H NMR (CDCl₃) δ: 6.37 (d, J=11 Hz, 1 H), 6.01 (d, J=11 Hz, 1 H), 5.37(m, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.41-4.45 (m, 1 H), 4.22-4.24(m, 1 H), 4.06 (br., 1 H), 2.80-2.85 (m, 1 H), 2.58-2.63 (m, 1 H), 1.19(s, 3 H 0.85-2.35 (m, 19 H), 0.97 (d, J=6.5 Hz, 3 H), 0.57 (s, 3 H).

Example 29

Production of Compounds No. 1426c and No. 1426d ##STR23##

The objective compounds were produced in the same way as in Example 28except that ketone [Q] was used in place of the ketone [N]. Thecompounds are optical isomers originated from the asymmetric carbonbound to which the hydroxyl group formed by the reduction reaction ofthe ketone in this example is bound.

[Compound No. 1426c] (obtained from the fraction of a lower polarity ofsilica gel column chromatography)

¹ H NMR (CDCl₃) δ: 6.38 (d, J=7.0 Hz, 1 H), 6.02 (d, J=7.0 Hz, 1 H),5.39 (d, J=12 Hz, 1 H), 5.32 (s, 1 H), 5.00 (s, 1 H), 4.44 (br., 1 H),4.23 (br., 1 H), 3.89 (br., 1 H), 3.49 (s, 1 H), 2.83 (m, 1 H),0.93-3.49 (m, 20 H), 1.26 (s, 3 H), 0.99 (d, J=6.5 Hz, 3 H) , 0.57 (s, 3H).

[Compound No. 1426d] (obtained from the fraction of a higher polarity ofsilica gel column chromatography)

¹ H NMR (CDCl₃) δ: 6.37 (d, J=7.0 Hz, 1 H), 6.01 (d, J=7.0 Hz, 1 H),5.37 (m, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.45 (m, 1 H), 4.23 (m, 1H), 4.08 (br., 1 H), 2.83 (m, 1 H), 2.69 (m, 1 H),1.01-2.33 (m, 19 H),1.17 (s, 3 H), 1.00 (d, J=6.6 Hz, 3 H), 0.57 (s, 3 H).

Example 30

Production of Compound No. 1716 ##STR24##

The aldehyde [J], which had been produced in Reference Example 1, andketone [R] were converted into an aldol adduct [S] according to a methodsame as in Example 12. According to the method same as in Example 25,the obtained adduct [S] was reduced to obtain a pair of alcohols [T]having a lower polarity and a higher polarity. The alcohols were allowedto couple with [H] according to the same method as in Example 12, andthe reaction products were subjected to deprotection reaction to obtainthe objective products. They are optical isomers originated from theasymmetric carbon bound to which the hydroxyl group formed by thereduction reaction of the ketone in this example is bound.

[Compound No. 1716a] (obtained from the fraction of a lower polarity ofsilica gel column chromatography)

¹ H NMR (CDCl₃) δ: 6.33 (d, J=12 Hz, 1 H), 6.09 (d, J=11 Hz, 1 H), 5.29(dd, J=1.3, 2.3 Hz, 1 H), 4.90 (d,, J=1 Hz, 1 H), 4.35 (br., 1 H), 4.07(br., 1 H), 3.56 (d, J=10 Hz, 1 H), 3.29-3.31 (m, 2 H), 1.2-2.9 (m,25H), 1.00 (s, 3 H), 0.93 (d, J=6 Hz, 3 H), 0.92 (s, 3 H), 0.57 (s, 3H).

[Compound No. 1716b] (obtained from the fraction of a higher polarity ofsilica gel column chromatography)

¹ H NMR (CDCl₃) δ: 6.33 (d, J=11 Hz, 1 H), 6.09 (d, J=11 Hz, 1 H), 5.30(t, J=1.6 Hz, 1 H), 4.91 (d, J=1.6 Hz, 1 H), 4.36 (t, J=6 Hz, 1 H), 4.13(br., 1 H), 3.82 (d, J=10 Hz, 1 H), 3.64 (d, J=4 Hz, 1 H), 3.31 (t,J=1.7 Hz, 2 H), 1.25-2.90 (m, 24 H), 1.04 (s, 3 H), 0.95 (s, 3 H), 0.93(d, J=7 Hz, 3 H), 0.57 (s, 3 H).

Example 31

Production of Compound No. 1126e ##STR25##

The compound No. 1126b (41 mg) was dissolved in 5 ml of toluene and 5 mlof ethanol, and the obtained solution was irradiated with ultravioletrays of 350 nm for 6 hr in nitrogen atmosphere after the addition ofanthracene (38.5 mg) and triethylamine (3 ml). The treated solution wasconcentrated under reduced pressure, the concentrate was purified bysilica gel column chromatography and further by HPLC to obtain theobjective product.

¹ H NMR (CDCl₃) δ: 6.37 (d, J=11 Hz, 1 H), 6.02 (d, J=11 Hz, 1 H), 5.62(dt, J=2, 11 Hz, 1 H), 5.32 (m, 1 H), 4.99 (s, 1 H), 4.42 (m, 1 H), 4.22(m, 1 H), 3.69-3.75 (m, 2 H), 1.24 (m, 3 H), 1.28-2.82 (m, 22 H), 0.99(d, J=6 Hz, 3 H), 0.63 (s, 3 H).

Example 32

Production of Compound No. 1126f

The objective compound was produced using the compound No. 1126c in thesame way as in Example 31.

¹ H NMR (CDCl₃) δ: 6.34 (d, J=10 Hz, 1 H), 5.96-6.02 (m, 2 H), 5.32 (m,1 H), 4.98 (s, 1 H), 4.43 (m, 1 H), 4.22 (m, 1 H), 3.73 (m, 1 H), 3.58(m, 1H), 1.22 (m, 3 H), 1.18-2.83 (m, 22 H), 0.96 (d, J=6 Hz, 3 H), 0.36(s, 3H).

Example 33

Production of Compound No. 1105b

The objective compound was produced in the same way as in Example 31using the compound No. 1105a.

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11 Hz, 1 H), 6.01 (d, J=10 Hz, 1 H), 5.60(m, 1 H), 5.32 (s, 1 H), 5.00 (s, 1 H), 4.43 (m, 1 H), 4.23 (m, 1 H),1.22-2.85 (m, 29 H), 0.91 (d, J=6 Hz, 3 H), 0.55 (s, 3 H).

Example 34

Production of Compound No. 1606a ##STR26##

According to the method of Example 12, aldehyde [U] and ketone [V] weremade to react with each other to obtain alcohol [W].

A solution of titanium tetraisopropoxide (69.1 mg) in 2 ml of methylenechloride was cooled to -23° C. in the presence of molecular sieve 4A(100 mg), and a solution of L-(+)-tartaric acid diisopropyl ester (68.8mg) in 2 ml of methylene chloride was added to the above solution, andsubsequently a solution of the alcohol [W] (106 mg) in 2 ml of methylenechloride was added. Further, 0.044 ml of a 3M solution oft-butylhydroperoxide in 2,2-dimethyl-4-methylpentane was added, and themixture was stirred for 2 hr. After the addition of methanol, asaturated sodium bicarbonate aqueous solution and a saturated sodiumthiosulfate aqueous solution were added, and the mixture was warmed upto room temperature. The reaction mixture was filtered through celite,the filtrate was extracted with ethyl acetate. The combined organiclayer was washed with brine, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to obtain[X].

A solution of the obtained [X] (41.8 mg) in 2 ml of diethyl ether wasadded to a suspension of lithium aluminum hydride (5.5 mg) in 0.5 ml ofdiethyl ether, and further lithium aluminum hydride (6.6 mg) was addeduntil [X] was disappeared. A saturated sodium sulfate aqueous solutionwas added to the reaction mixture to stop the reaction until hydrogengeneration ceased, and after diluted with diethyl ether, the reactionmixture was filtered through celite to remove insoluble matters, and theinsoluble matters were further washed with ethyl acetate. The combinedorganic layer was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography to obtain [Y].

To the ice-cold solution of [Y ] (13.7 mg) in methylene chloride wasadded about 3 ml of an oxidant, which had been prepared from sulfurtrioxide pyridine complex, dimethyl sulfoxide, triethylamine andmethylene chloride at ratios of 50.9 mg : 0.109 ml: 0.152 ml: 1 ml. Themixture was stirred for 8 hr, water was added to stop the reaction, andthe reaction mixture was extracted with ethyl acetate. The combinedorganic layer was washed sequentially with a saturated potassiumhydrogen sulfate aqueous solution, water and brine, dried over sodiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography to obtain [Z].

The obtained [Z] was subjected to a coupling reaction with an ene-ynecompound by the same method as in Example 12, and the product wastreated for deprotection to obtain the objective product. ¹ H NMR(CDCl₃) δ: 6.38(d, J=10.9 Hz, 1 H), 6.01 (d, J=11.2 Hz, 1 H), 5.33 (s, 1H), 5.00 (s, 1 H), 4.41-4.45 (m, 1 H), 4.23-4.25 (m, 1 H), 3.97 (s, 1H), 2.80-2.84 (m, 1 H), 0.92-2.62 (m, 30 H), 0.90 (d, J=6.3 Hz, 3 H),0.53 (s, 3 H).

Example 35

Production of Compound No. 1606b

The objective compound was obtained by using L-(-)-tartaric aciddiisopropyl in stead of L-(+)-tartaric acid diisopropyl in the stage ofthe epoxidation in Example 34. This compound is the optical isomer ofthe compound No. 1606a originated from the asymmetric carbon to whichthe hydroxyl group formed by the ring opening reaction of the epoxy ringin the present example is bound.

¹ H NMR (CDCl₃) δ: 6.38 (d, J=11.2 Hz, 1 H), 6.01 (d, J=11.2 Hz, 1 H),5.33 (s, 1 H), 5.00 (s, 1 H), 4.43 (dd, J=4.6, 7.6 Hz, 1 H), 4.20-4.26(m, 1 H), 3.98 (s, 1 H), 2.82(dd, J=3.3, 11.9 Hz, 1 H), 2.60 (dd, J=3.5,13.4 Hz, 1 H), 2.46-2.50 (m, 2 H), 0.76-2.35 (m, 26 H), 0.90 (d, J=5.9Hz, 3 H), 0.53 (s, 3 H).

Example 36

Production of Compound No. 1132 ##STR27##

The 1,3-TBS protected compound (67 mg) of the compound No. 1126cobtained in Example 5 was dissolved in 1.5 ml of chloroform. To theresultant solution were added triethylamine (80 mg), acetyl chloride (48mg) and dimethylaminopyridine (12 mg), and the mixture was stirred atroom temperature for 5 hr. The reaction mixture was purified by silicagel column chromatography to obtain [A]. The product was dissolved in1.5 ml of methanol, PPTS polymer (5 mg) was added, and the mixture wasstirred at room temperature overnight. The reaction mixture wasfiltered, the filtrate was concentrated, and the residue was purified byHPLC to obtain the objective product.

¹ H NMR (CDCl₃) δ: 6.60 (d, J=10.7 Hz, 1 H), 6.37 (d, J=11.1 Hz, 1 H),6.00 (d, J=10.7 Hz, 1 H), 5.32 (s, 1 H), 4.99 (s, 1 H), 4.45 (br., 1 H),4.22 (br., 1 H), 2.56-2.81 (m, 3 H), 2.26-2.41 (m, 4 H), 1.87-2.07 (m, 5H), 2.04 (s, 3 H), 1.19-1.78 (m, 11 H), 1.38 (s, 3 H), 0.97 (d, J=6.4Hz, 3 H), 0.46 (s, 3 H).

Example 37

Production of Compound No. 1138

According to a method similar to Example 36, the objective compound wasproduced by using butanoyl chloride in stead of the acetyl chloride.

¹ H NMR (CDCl₃) δ: 6.59 (d, J=10.6 Hz, 1 H), 6.37 (d, J=11.4 Hz, 1 H),6.00 (d, J=11.2 Hz, 1 H), 5.32 (t, J=1.7 Hz, 1 H), 4.99 (s, 1 H), 4.43(br., 1 H), 4.22 (br., 1 H), 2.69-2.82 (m, 2 H), 2.40-2.62 (m, 1 H),2.24-2.39 5 H), 1.68-2.06 (m, 6 H), 1.13-1.65 (m, 16 H), 0.97 (d, J=6.6Hz, 3 H), 0.93 (t, J=7.3 Hz, 3 H), 0.46 (s, 3 H).

Example 38

Neutrophilic Infiltration Suppressing Effect Assayed by Using HamsterLPS-Induced Airway Inflammatory Model

A male golden hamster is placed in an inhalation chamber (volume: 12liter) and allowed to inhale LPS (nebulizer filled concentration: 2.0mg/ml) generated by an ultrasonic nebulizer for 30 min to cause airwayinflammatory. Just after the inhalation of the LPS, a compound of thepresent invention is administered through intrarespiratory tractadministration or orally at a dosage of 20 μg/kg under halothaneanesthesia. After 24 hr, tracheal branches and pulmonary alveoli werewashed, and the number of neutrophils in the washing were determined.Using the number of neutrophils obtained in the absence of a compound ofthe present invention as the control, the decreasing rates of thenumbers of neutrophils were expressed in terms of percent suppressionbased on the control.

The results are shown in Table 3 (intrarespiratory tract administration)and in Table 4 (oral administration).

                  TABLE 3                                                         ______________________________________                                        Neutrophilic infiltration suppressing effect assayed by using hamster          LPS-induced airway inflammatory model (intrarespiratory tract                 administration)                                                                % Suppression                                                                            Compound No.                                                     ______________________________________                                        >40%     1105b, 1107, 1110b, 1112a, 1112b, 1116*, 1126a,                         1126b, 1126c, 1126e, 1126f, 1127a, 1144b, 1144d,                              1156a, 1156b, 1226, 1401a, 1606a, 2101, 2104a                                20-40% 1426c*, 1129d*, 1716a, 1128b, 1126d                                    <20% 1101                                                                   ______________________________________                                         *assayed at a dosage of 1 μg/kg                                       

                  TABLE 4                                                         ______________________________________                                        Neutrophilic infiltration suppressing effect assayed by using hamster          LPS-induced airway inflammatory model (oral administration)                    % Suppression      Compound No.                                             ______________________________________                                        >40%             1116, 1126b, 1226, 2104a                                       20-40% 1110b                                                                  <20%                                                                        ______________________________________                                    

This model is widely used as an inflammatory pulmonary disease model(Esbenshade, A. M., et al., J. Appl. Physiol., 53, 967-976 (1982)), andit has been reported that the model exhibits a morbid state of acuteaggravation of an inflammatory pulmonary disease (Hurlar, L. M., et al.,J. Appl. Physiol., 54, 1463-1468 (1983)).

From the results of Table 3 and Table 4, it has been found thatcompounds of the present invention have neutrophilic infiltrationsuppressing effect in the model. These results have demonstrated thatcompounds of the present invention are effective as treating agents forinflammatory respiratory diseases.

Example 39

Differentiation Induction Effect to Human Leukemia Cell, HL-60 Cell

HL-60 cell line that had been purchased from a cell bank was used. Thecell line was stored as a frozen storage stock for preventing the changeof cell characteristics attributable to successive cultivations. Priorto the initiation of experiments, the cells were defrosted andsuccessive culturing was stared, and such cells were used. Thesuccessive culturing was carried out by centrifugally recovering cellswhich were in the state of suspension culture, and diluting thecollected cell concentrate by a fresh culture medium at a ratio of about1/100 (1-2×10⁴ cells/ml). As the culture medium, an RPMI-1640 mediumcontaining 10% fetal bovine serum was used. Thus, cells which were inthe successive culturing were centrifugally collected, and they weredispersed in a culture medium at the concentration of 2×10⁴ cells/ml.The dispersion was seeded into a 24-well culture schale at 1 ml/well. Anethanol solution (1×10⁻⁵ M) of a compound of the present invention wasadded to this system at 1 μl/well (the final concentration of thecompound: 1×10⁻⁸ M). For the control, ethanol was added at 1 μl/well.After culturing at 37° C. for 4 days in 5% CO₂ atmosphere, the cellswere centrifugally collected.

Nitroblue tetrazolium (NBT) reduction activity was determined asfollows. That is, the centrifugally collected cells were suspended in afresh culture medium, and NBT and 12-O-tetradecanoylphorbol-13-acetate(TPA) were added to the resultant suspension so that theirconcentrations became 0.1% and 100 nM, respectively. After the mixedsuspension was incubated at 37° C. for 25 min, a cytospin sample wasprepared. After air drying, it was stained with Kernechtrot, and theratio of the positive cells of NBT reduction activity was determinedunder an optical microscope. The results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        Differentiation induction effect to human leukemia cell, HL-60 cell             Ratio of cells positive in NTB                                                                   reduction activity Compound No                           ______________________________________                                        >50%            1126b, 1129d, 1131a, 1131b                                      10-50% 1127a, 1128a, 1128b, 1129b, 1130a                                      <10% 1126d, 1127b, 1130b                                                    ______________________________________                                    

Thus, it has been found that compounds of the present invention havedifferentiation induction effect to tumor cell.

Example 40

Growth Suppression Effect to Human Colon Cancer Cell, HT-29 Cell

HT-29 cell Line that had been purchased from a cell bank was used. Thecell line was stored as a frozen storage stock for preventing the changeof cell characteristics attributable to successive cultivations. Priorto the initiation of experiments, the cells were defrosted andsuccessive culturing was stared, and such cells were used. Thesuccessive culturing was carried out by centrifugally recovering cellswhich were in the state of suspension culture, and diluting thecollected cell concentrate by a fresh culture medium at a ratio of about1/100 (1-2×10⁴ cells/ml). As the culture medium, an RPMI-1640 mediumcontaining 10% fetal bovine serum was used. Thus, cells which were inthe successive culturing were centrifugally collected, and they weredispersed in a culture medium at the concentration of 2.5×10³ cells/ml.The dispersion was seeded into a schale of 35 mm in diameter at anamount of 2 ml/shale. A 1×10⁻⁴ to 1×10⁻³ M ethanol solution of thecompound No. 1126b, as a compound of the present invention, was added tothis system in an amount of 2 μl to every schale (the finalconcentration of the compound : 1×10⁻⁷ to 1×10⁻⁶ M). For the control,ethanol was added at a ratio of 2 μl per schale. After culturing at 37°C. for 10 days in 5% CO₂ atmosphere, the culture medium was removed, andthe cells were washed with PBS and fixed on the schale with a 10%formalin buffer solution. The cells were washed with water, air-driedand stained with a crystal violet solution. After dyeing, the cells werewashed with water and air-dried. The relative absorbance (vs. 100 of theabsorbance of the schale of the control) of the schale of the compoundwas measured to determine the relative cell growth rate. The results areshown in Table 6.

                  TABLE 6                                                         ______________________________________                                        Growth suppression effect to human colon cancer cell, HT-29 cell                                          Relative degree of cell                               growth (%)                                                                  Compound Concentration (M) mean ± SD (n = 4)                             ______________________________________                                        Control    --           100                                                     No. 1126b 10.sup.-7 85.5 ± 1.9                                              5 × 10.sup.-7 63.0 ± 1.6                                             10.sup.-6 59.0 ± 0.0                                                    ______________________________________                                    

The above results show that a compound of the present invention candose-relatedly suppress the growth of cancer cells.

Example 41

Effect on the Increase of Blood Calcium Concentration in Repeated OralAdministration to Rats

Male SD rats (6 weeks of age, Japan SLC, inc.) were used. Feed foranimal raising (MF, Oriental Yeast Industry Co. Ltd.) and water (wellwater treated with 0.4±0.2 ppm of hypochlorite) were given ad libitumtrough out the experiment. The animals were housed individually insuspension-type rat cages and raised at 24±2° C. at a relative humidityof 55±5%. A control group was orally administered pure vehicle (0.1%Triton X-100) for 2 weeks. Active groups were orally administered 1 α,25(OH)₂ D₃ in an amount of 0.1-0.5 μg/kg/day or the compound No. 1126bof the present invention in an amount of 2-10 μg/kg/day, as test agentsfor 2 weeks. After about 24 hr of the final administration, blood wascollected from an eyeground under ether anesthesia using a heparinizedglass micro capillary, and the calcium concentration in the separatedplasma was determined by an autoanalyzer (model AU-600, Olympus). Theresults are shown in Table 7.

                  TABLE 7                                                         ______________________________________                                        Effect on the increase of blood calcium concentration in repeated oral         administration to rats                                                                       Dose      Blood Ca conc. (mg/dl)                                                         Compound (μg/kg/day) mean ± SD               ______________________________________                                        Control     --        10.7 ± 0.4 (n = 5)                                     1α,25(OH).sub.2 D.sub.3 0.1 10.7 ± 0.1 (n = 5)                        0.5   11.6 ± 0.1 (n = 3)**                                                No. 1126b 2 10.6 ± 0.4 (n = 5)                                              10 11.1 ± 0.3 (n = 5)                                                   ______________________________________                                         **Statistically significant difference to the control group is observed       (Dunnett's test, 1% in significance level)                               

While the calcium concentration in the control group was about 10.7mg/dl, the calcium concentration was clearly increased to about 11.6mg/dl in the 1 α, 25(OH)₂ D₃ administration group at a dose of 0.5μg/kg/day. On the other hand, in the compound No. 1126b administrationgroup, the increase of the calcium concentration was not observed at allat a dose of 2 μg/kg/day, and the slight increase of the calciumconcentration was observed at a dose of 10 μg/kg/day, the differencebeing not statistically significant.

From the result, it has been found that the effect on the increase ofblood calcium concentration in repeated oral administration of acompound of the present invention is extremely reduced compared with 1α, 25(OH)₂ D₃.

Example 42

Anti-Malignant Tumor Effect and Blood Calcium Concentration IncreaseEffect using Mouse which has been Transplanted Tumor Cells under theRenal Capsule

Male ICR mice (6 weeks of age, Carles River Japan Ltd.) were used. Feedfor animal raising (MF, Oriental Yeast Industry Co. Ltd.) and water(well water treated with 0.4±0.2 ppm of hypochlorite) were given adlibitum trough out the experiment. The animals were housed inpolycarbonate-made raising cages and raised at 23±1° C. at a relativehumidity of 55±10%. As the human malignant tumor cells to betransplanted under the renal capsule, HL-60 cell line used in Example 39and HT-29 cell line used in Example 40 were used. The transplantationunder the renal capsule and the evaluation of the growth suppressingeffect of transplanted malignant tumor cell conglomerates were carriedout according to the methods of Fingert, et al. (Cancer Res., 47,3824-3829 (1987)) and Tanaka, et al. (Cancer Res., 54, 5148-5153(1994)). The day before the operation, cyclophosphamide (150 mg/kg) wasintraperitoneally administered to the mice. The HL-60 cells and HT-29cells to be transplanted were treated according to the following methodto form fibrin coagulates. That is, cells were centrifugally collected,washed with a phosphate buffer solution, then suspended in a serum freeRPMI-1649 medium and incubated at 37° C. for 10 min after the additionof fibrinogen (20 mg/ml) and thrombin (20 U/ml). Solidified cellaggregates were finely cut into cubes of about 1.5 mm under astereoscopic microscope equipped with an ocular micrometer. The finelycut cell aggregates were preserved in an ice-cooled RPMI- 1640 mediumbefore the transplantation. The transplantation was performed by cuttingthe left rear back side of a mouse under nembutal anesthesia about 1 cmwide, pulling out the left kidney, forming a small cut line on it, andinserting a cell aggregate under renal capsule from the cut line byusing a transplantation needle (Natsume Ltd.). From the next day of theoperation, cyclosporin A (100 mg/kg) was intraperitoneally administeredto all the animals. A control group was orally administered pure vehicle(0.1% Triton X-100) for 2 weeks. Active groups were orally administered1 α, 25(OH)₂ D₃ in an amount of 1 μg/kg/day or the compound No. 1126b ofthe present invention in an amount of 10 or 20 μg/kg/day, as testagents, for 2 weeks. After about 24 hr of the final administration,blood was collected from the heart under nembutal anesthesia, and thecalcium concentration in the separated serum was determined by anautoanalyzer (model 7070, Hitachi, Ltd.). Further, after the bloodcollection from the heart, the left kidney was taken out and fixed witha 10% neutral buffer formalin solution, and the size of the implantedmalignant tumor cell aggregate was determined under a stereoscopicmicroscope using a micrometer. As an indicator of the size of thetransplanted cell aggregate, a tumor area (the scale of the micrometerof the aggregate in the renal major axis direction × the scale of themicrometer of the aggregate in the renal minor axis direction) was used.

The results of the blood calcium concentrations determined are shown inFIG. 1, and the results of the studies of the growth suppressing effectof the transplanted malignant tumor cells are shown in FIG. 2(transplantation of HL-60) and in FIG. 3 (transplantation of HT-29).

In the 1 α, 25(OH)₂ D₃ administration group, growth suppressing effectsare observed both in cases of HL-60 cell and HT-29 cell as shown in FIG.2 and FIG. 3, and the blood calcium level has been extremely increasedcompared with the control as shown in FIG. 1.

On the other hand, in the compound No. 1126b administration group,growth suppressing effects are observed both in cases of HL-60 cell andHT-29 cell, and the blood calcium increasing effect at theseconcentrations are observed at only slight degree.

Thus, the results of Examples 39-42 show that compounds of the presentinvention have differentiation inducing effects and growth suppressingeffects on malignant tumor cells in vitro, and have elevation effects onblood calcium levels which are extremely reduced compared with that of 1α, 25(OH)₂ D₃ in vivo, and further they have growth suppressing effectson transplanted malignant tumor cells at doses which scarcely showelevation effects on blood calcium concentration. By these findings, ithas been demonstrated that compounds of the present invention areeffective as treating agents for malignant tumors.

Example 43

Production of Tablets

Tablets, each compound of the following components, were produced.

    ______________________________________                                        The compound No. 1144b                                                                           50 mg                                                        Lactose 230 mg                                                                Potato starch 80 mg                                                           Polyvinylpyrrolidone 11 mg                                                    Magnesium stearate  5 mg                                                    ______________________________________                                    

A compound (compound No. 1144b) of the present invention, lactose andpotato starch were mixed. The mixture was homogeneously wetted with 20%solution of polyvinylpyrrolidone in ethanol, passed through a 20-meshsieve, dried at 45° C. and passed again through a 15-mesh sieve. To thusobtained granules was added magnesium stearate, and the mixture wascompressed to tablets.

Industrial Field of Application

Medicines containing vitamin D₃ derivatives expressed by the aboveformula [1] of the present invention as active ingredients can be usedfor treating inflammatory respiratory diseases.

Further, medicines containing vitamin D₃ derivatives expressed by theabove formula [1] of the present invention as active ingredients can beused for treating malignant tumors.

On the other hand, the blood calcium level increasing effects of vitaminD₃ derivatives of the present invention have been extremely reducedcompared with that of 1 α, 25-dihydroxyvitamin D₃.

Furthermore, vitamin D₃ derivatives expressed by the above formula [1]of the present invention have immunosuppressive effects such as thestimulation of maturation and differentiation of a cell, and theinhibition of interleukin-2 production, and the derivatives further haveeffects to stimulate the production of microbicidal oxygen metaboliteand the chemotactic reaction of a leukocyte as immunological synergisticeffect. Medicines containing vitamin D₃ derivatives of the presentinvention as active ingredients can therefore be agents for treatingpsoriasis, rheumatoid arthritis, inflammatory diseases such asdermatitis and autoimmune diseases, supplementary agents in chemotherapyfor infections, and treating agents in therapeutic phases to whichmononuclear phagocytes are associated.

Besides these diseases, medicines containing vitamin D₃ derivatives ofthe present invention as active ingredients can be used also fortreating hypertension, diabetes mellitus, acne or osteoporosis, orstimulating hair growth.

We claim:
 1. A vitamin D₃ derivative expressed by the following generalformula (1) ##STR28## wherein, Z is 1a, 1b or 1c; R₁ and R₂ areidentical to or different from each other, and are each a hydrogen atom,a tri(C₁ -C₇ alkyl)silyl group, an acetyl group, a methoxymethyl group,or a tetrahydropyranyl group; R₃ and R₄ are identical to or differentfrom each other, and are each a hydrogen atom, a hydroxyl group, a C₂-C₈ acyloxy group, a C₁ -C₇ alkyloxy group, a C₁ -C₆ alkylthio group ora C₁ -C₇ alkyl group which is optionally substituted with a hydroxylgroup, a C₂ -C₈ acyloxy group or a C₁ -C₇ alkyloxy group; R₅, R₆, R₇ andR₈ are identical to or different from each other, and are each ahydrogen atom, a hydroxyl group, a C₁ -C₇ alkyl group or a C₂ -C₈acyloxy group; R₉ is a hydrogen atom, a hydroxyl group, a C₁ -C₇ alkylgroup or a C₁ -C₆ alkylthio group; R₁₀ is a hydrogen atom, a C₁ -C₇alkyl group or a C₁ -C₇ alkyloxy group; A and B are identical to ordifferent from each other, and are each a hydrogen atom, a hydroxylgroup, or together express a single bond and express a double bond incooperation with the single bond already shown in the formula; X and Ytogether express (i) a carbonyl group in cooperation with the carbonatom to which they are bonded, (ii) one of them is a hydrogen atom andthe other is a hydroxyl group, or (iii) one of them is a hydrogen atomand the other is a C₂ -C₈ acyloxy group; n is an integer of 0 to 2; m isan integer of 0 to 2; or a pharmaceutically permissible solvate thereof.2. A vitamin D₃ derivative or a pharmaceutically permissible solvatethereof as claimed in claim 1, wherein both of R₁ and R₂ in the aboveformula (1) are hydrogen atoms.
 3. A vitamin D₃ derivative or apharmaceutically permissible solvate thereof as claimed in claim 1 orclaim 2, wherein Z in the above formula (1) is (1a) or (1b).
 4. Avitamin D₃ derivative or a pharmaceutically permissible solvate thereofas claimed in claim 1 or claim 2, wherein Z in the above formula (1) is(1a).
 5. A vitamin D₃ derivative or a pharmaceutically permissiblesolvate thereof as claimed in claim 1 or claim 2, wherein Z in the aboveformula (1) is (1b).
 6. A vitamin D₃ derivative or a pharmaceuticallypermissible solvate thereof as claimed in claim 1 or claim 2, wherein Zin the above formula (1) is (1c).
 7. A vitamin D₃ derivative or apharmaceutically permissible solvate thereof as claimed in claim 1,wherein both of R₇ and R₈ in the above formula (1) are each a hydrogenatom or a C₁ -C7 alkyl group.
 8. A vitamin D₃ derivative or apharmaceutically permissible solvate thereof as claimed in claim 1,wherein both of R₅ and R6 in the above formula (1) are each a hydrogenatom or a C₁ -C₇ alkyl group.
 9. A vitamin D₃ derivative or apharmaceutically permissible solvate thereof as claimed in claim 1,wherein both of A and B in the above formula (1) are each a hydrogenatom or together express a single bond and express a double bond incooperation with the single bond already shown in the formula.
 10. Avitamin D₃ derivative or a pharmaceutically permissible solvate thereofas claimed in claim 1, wherein m in the above formula (1) is 0 or
 1. 11.A vitamin D₃ derivative or a pharmaceutically permissible solvatethereof as claimed in claim 1, wherein n in the above formula (1) is 0or
 1. 12. A vitamin D₃ derivative or a pharmaceutically permissiblesolvate thereof as claimed in claim 1, wherein, in the above formula(1),(a) either of R₃ and R₄ is a hydroxyl group, and the other is a C₁-C₇ alkyl group optionally substituted with a hydroxyl group, a C₂ -C₈acyloxy group or a C₁ -C₇ alkyloxy group; (b) either of R₃ and R₄ is ahydrogen atom, and the other is a C₁ -C₇ alkyl group optionallysubstituted with a hydroxyl group, a C₂ -C₈ acyloxy group or a C₁ -₇alkyloxy group; (c) both of R₃ and R₄ are each a hydrogen atom, or (d)both of R₃ and R₁ are each a C₁ -C₇ alkyl group optionally substitutedwith a same or different group selected from the group consisting of ahydroxyl group, a C₂ -C₈ acyloxy group and a C₁ -C7 alkyloxy group. 13.A treating agent for an inflammatory respiratory disease containing atherapeutically effective amount of a vitamin D₃ derivative or apharmaceutically permissible solvate thereof as claimed in claim
 1. 14.A treating agent for an inflammatory respiratory disease as claimed inclaim 13, wherein the inflammatory respiratory disease is one or notless than two inflammatory respiratory diseases selected from a groupconsisting of acute upper airway infection, chronic sinusitis, allergicrhinitis, chronic lower airway infection, pulmonary emphysema,pneumonia, asthma, pulmonary tuberculosis sequela, acute respiratorydistress syndrome and pulmonary fibrosis.
 15. A treating agent forinflammatory respiratory disease as claimed in claim 14, wherein theacute upper airway infection is one or not less than two kinds ofdiseases selected from a group consisting of common cold, acutepharyngitis, acute rhinitis, acute sinusitis, acute tonsillitis, acutelaryngitis, acute epiglottitis and acute bronchitis.
 16. A treatingagent for inflammatory respiratory disease as claimed in claim 14,wherein the chronic lower airway infection is one or not less than twokinds of diseases selected from a group consisting of chronicbronchitis, diffuse panbronchiolitis and bronchiectasis.
 17. A treatingagent for one or not less than two kinds of acute upper airwayinfections selected from the group consisting of common cold, acutepharyngitis, acute rhinitis, acute sinusitis, acute tonsillitis, acutelaryngitis, acute epiglottitis and acute bronchitis containing atherapeutically effective amount of a vitamin D₃ derivative or apharmaceutically permissible solvate thereof as claimed in claim
 1. 18.A treating agent for one or not less than two kinds of chronic lowerairway infections selected from the group consisting of chronicbronchitis, diffuse panbronchiolitis and bronchiectasis containing atherapeutically effective amount of a vitamin D₃ derivative or apharmaceutically permissible solvate thereof as claimed in claim
 1. 19.A treating agent for a malignant tumor containing a therapeuticallyeffective amount of a vitamin D₃ derivative or a pharmaceuticallypermissible solvate thereof as claimed in claim
 1. 20. A treating agentfor a disease selected from a group consisting of rheumatoid arthritis,osteoporosis, growth diabetes mellitus, hypertension, alopecia, acne,psoriasis and dermatitis containing a therapeutically effective amountof a vitamin D₃ derivative or a pharmaceutically permissible solvatethereof as claimed in claim
 1. 21. A pharmaceutical composition composedof a vitamin D₃ derivative or a pharmaceutically permissible solvatethereof as claimed in claim 1 and a pharmaceutically permissiblecarrier.
 22. A method for producing an active vitamin D₃ derivative or apharmaceutically permissible solvate thereof as claimed in claim 1consisting of treating a vitamin D₃ with hydroxyl groups at the first-and the third-positions protected with tri(C₁ -C₇ alkyl)silyl groupswith a reagent comprising a combination of a tetrafluoroborate alkalimetal salt and then a mineral acid for deprotection.
 23. A method forproducing an active vitamin D₃ derivative as claimed in claim 1, whereinR₁ and R₂ are each a tri(C₁ -C₇ alkyl)silyl group.